Progress in Retinal and Eye Research 39 (2014) 77e106Contents lists available at ScienceDirect Progress in Retinal and Eye Research journal homepage: www.elsevier.com/locate/prer Ocular toxoplasmosis past, present and new aspects of an old disease M. Maenz a,1, D. Schlüter b,1, O. Liesenfeld c,1, G. Schares d,1, U. Gross e,1, U. Pleyer a, *,1 a Eye Clinic e Charité Universitaetsmedizin-Berlin, Augustenburger Platz 1, 13353 Berlin, Germany Institute of Medical Microbiology, Otto-von-Guericke-University Magdeburg, Germany c Institute for Microbiology and Hygiene, Charité Universitaetsmedizin-Berlin, Germany d Institute of Epidemiology e Friedrich-Loeffler-Institute e Greifswald-Insel Riems, Germany e Institute for Medical Microbiology and German Consulting Laboratory for Toxoplasmosis, University Medical Center Goettingen, Germany b a r t i c l e i n f o Article history: Available online 9 January 2014 Keywords: Ocular toxoplasmosis Uveitis Toxoplasma gondii Retinochoroiditis a b s t r a c t Ocular toxoplasmosis (OT) is considered the most frequent form of infectious posterior uveitis and is caused by the protozoan parasite Toxoplasma gondii. The resulting vision loss frequently incapacitates patients and places a considerable socio-economic burden on societies in particular in developing countries. Although, toxoplasmic retinochoroiditis is a world-wide phenomenon stark regional differences with regard to prevalence and presumably route of infection exist. This review will discuss our current clinical understanding of OT including typical and atypical manifestations, patient characteristics which influence the course of disease and treatment options. Even though, congenital and acquired OT are not regarded as separate entities, certain differences exist, which will be assessed and evaluated in detail. A strong focus is laid on the disease causing parasite T. gondii, since solving the mystery of OT aetiology and the development of improved therapies will not be possibly with clinical science alone, but rather requires a precise understanding of parasitological and immunological pathomechanisms. Additionally, the biology and genetics of T. gondii form the foundation for novel and sophisticated diagnostic methods. Scientific advances in the recent years have shed some light on the different role of T. gondii strains with regard to OT manifestation and severity of disease. Genetic and environmental factors influencing OT will be presented and commonalities between OT and toxoplasmic encephalitis will be briefly discussed. Furthermore, the laboratory tools to study OT are crucial in our understanding of OT. In vivo and in vitro experimental approaches will be summarised and evaluated extensively. Finally, a brief outlook is given in which direction OT research should be headed in the future. Ó 2014 Elsevier Ltd. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 1.1. Historical background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 1.2. Introduction to T. gondii biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 1.3. Prevalence of T. gondii infections and ocular toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Ocular toxoplasmosis e clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 2.1. Spectrum of clinical presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 2.1.1. Retinochoroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 2.1.2. Punctate outer retinal toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 2.1.3. Neuroretinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 2.1.4. Scleritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 2.1.5. Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 2.2. Congenital vs. acquired infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 2. * Corresponding author. Tel.: þ49 30 450 554202; fax: þ49 30 450 554900. E-mail address:
[email protected] (U. Pleyer). 1 Percentage of work contributed by each author in the production of the manuscript is as follows: Maenz: 30%; Schlüter: 15%; Liesenfeld: 10%; Schares: 7.5%; Gross: 7.5%; Pleyer: 30%. 1350-9462/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.preteyeres.2013.12.005 78 M. Maenz et al. / Progress in Retinal and Eye Research 39 (2014) 77e106 2.3. 3. 4. 5. Patient factors related to susceptibility and severity in ocular toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 2.3.1. Genetic host factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 2.3.2. Patients’ age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 2.3.3. Patient immune status e disease in immunocompromised individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 2.3.4. Other factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 2.4. Diagnosis e serology and intraocular investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 2.4.1. Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 2.4.2. Serological findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 2.4.3. Analysis of intraocular specimen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 2.5. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 2.5.1. Treatment goals and general considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 2.5.2. Current treatment indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 2.5.3. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 2.5.4. Alternative treatment approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 2.5.5. Future therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Epidemiology, parasitology and neuro-immunology of Toxoplasma gondii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .91 3.1. Parasitological considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 3.1.1. Route of infection, environmental and parasite related factors contributing to infection and disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 3.1.2. Classical clonotypes vs. emergence of atypical strains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 3.2. Immunology of T. gondii infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 3.3. Pathomechanisms and neuro-immunology of T. gondii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Experimental approaches to study ocular toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 4.1. Animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 4.1.1. Parasite entry/methods of infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 4.1.2. Onset of disease and manifestation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 4.1.3. Self-limitation of disease and recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 4.1.4. Pathogen strains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 4.1.5. Experimental manipulation of disease course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 4.1.6. Immunomodulation & immunosuppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 4.1.7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 4.2. In vitro experimental models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 4.2.1. Host cell response to parasite entry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 4.2.2. Parasite replication and infectious capabilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 5.1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 5.2. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 5.3. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 5.4. New diagnostic and detection options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 5.5. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 1. Introduction 1.1. Historical background To this day ocular toxoplasmosis (OT) remains a challenging ocular disease with many open questions with regard to disease manifestation, pathophysiology and its management. Our current understanding of OT evolved over the course of more than a century through careful clinical observation, epidemiological and parasitological studies. Retinochoroidal scars e a clinical hallmark of OT e were probably already depicted in the mid 19th century (Fig. 1). Toxoplasmic retinochoroiditis as part of the disease manifestation of congenital toxoplasmosis in a newborn was first described by the Czech ophthalmologist Janku in 1923, and was considered an established medical fact almost two decades later (Janku, 1923; Wolf et al., 1939). After discovery of the parasite by Nicolle in 1907 (Nicolle, 1907; Nicolle and Manceaux, 2009), OT was recognised as an ocular pathology in adults by Wilder as late as 1952 (Wilder, 1952b, a). The seminal work of Hogan sparked and defined research on OT for the better part of the next two decades (Hogan, 1950, 1956, 1958a, b; Hogan et al., 1957, 1964, 1958). Most notably, already at this time the first treatment regimes were introduced in the shape of the antimalarial drug pyrimethamine in combination with sulphonamides and corticosteroids, which are still the most frequently prescribed agents until today (Perkins et al., 1956; Ryan et al., 1954) [see Section 2.5]. Whereas in the past e and with very limited success e clinical researchers attempted to subcategorise OT based on clinical parameters such as localisation of lesions, severity of inflammation, age of first manifestation, mode of infection and type of complications, OT today is understood as a disease with a broad spectrum of manifestations. Regardless of whether toxoplasmic retinochoroiditis occurs in immunocompromised and immunocompetent patients respectively, or whether OT is acquired congenitally or postnatally, no clear distinction between disease entities can be observed. The dogma that OT is an exclusive congenital disease eroded in the 1980s and today it is well recognised that postnatally acquired infection and subsequent ocular inflammation is the most frequent form of OT (Gilbert and Stanford, 2000). Based on advances in the recent decades, we know that OT is the most frequent form of infectious posterior uveitis representing up to 85% of all cases (Talabani et al., 2010). Where data are available pronounced geographical differences in disease prevalence can be observed. Particularly high prevalences are reported for M. Maenz et al. / Progress in Retinal and Eye Research 39 (2014) 77e106 79 Fig. 1. Probably an early depiction of toxoplasmic retinochoroiditis taken following the invention of the ophthalmoscope. The initial interpretation of this finding in a handicapped child is not known. C.G.T. Ruete [taken from “Bildliche Darstellung der Krankheiten des menschlichen Auges” (Ruete, 1854) (Pleyer et al., 2007). South- and Latin America as well as Africa and parts of Asia, leading to speculations that a part from environmental and nutritional factors host and parasite genotype have a significant impact on the occurrence and clinical manifestation of OT [see Sections 3.1.1 and 3.1.2]. Similarly, environmental and socio-economic factors as well as alimentary habits influence the epidemiology of infection with Toxoplasma gondii in general. Current controversies surrounding OT still focus on the precise role of different strains of T. gondii, host factors (i.e. genetic disposition), the optimal diagnostic approach and treatment (i.e. usefulness of corticosteroids) and the benefit of antiparasitic prophylaxis to prevent recurrences. OT is still an under- and often misdiagnosed ocular pathology and increased efforts have to be undertaken to reduce the disease burden of OT. In the long term, the current treatment goal, which focuses entirely on the preservation of vision without a curative option and the prevention of recrudescence, is an incomplete solution. 1.2. Introduction to T. gondii biology T. gondii is an obligate intracellular protozoan parasite that belongs to the phylum apicomplexa, subclass coccidia. The parasite exists in different morphologic and metabolic stages: Oocysts are the product of the parasite’s sexual cycle in the intestine of all members of the felids (cat family) and release infectious sporozoites (Fig. 2). Tachyzoites are asexual forms that e through their rapid replication e damage host tissue, while cysts, which contain bradyzoites, represent the dormant stage of the parasite in tissues. During primary feline infection several million oocysts (10 Â 12 mm in size) are shed in the faeces. Following sporulation sporozoites are released and may infect new hosts when ingested, giving rise to the tachyzoite stage. Tachyzoites (2e4 mm wide and 4e8 mm long) are crescentic or oval and are rapidly multiplying obligate intracellular stages of the parasite. Tachyzoites enter all nucleated cells by active penetration and form an intracytoplasmic vacuole. Following repeated replication, host cells are disrupted and tachyzoites invade neighbouring cells. The tachyzoite form causes a strong inflammatory response and tissue destruction and is therefore responsible for clinical manifestations of the disease. Under the pressure of the immune system, tachyzoites are transformed into bradyzoites that form cysts. Bradyzoites persist inside cysts for the life of the host (Fig. 2). Bradyzoites are morphologically similar to tachyzoites but multiply slowly, express stage-specific molecules and are functionally different (Lyons et al., 2002; Weiss and Kim, 2000). Tissue cysts containing between hundreds and thousands of bradyzoites are found in the retina, brain, skeletal and heart muscles. In immunocompromised patients bradyzoites may be released from cysts, transform back into tachyzoites and cause reactivation of the infection. Tissue cysts are infective stages for intermediate and definitive hosts via consumption of muscle or brain tissue. Humans can get infected by consumption of undercooked cyst-contaminated meat products or by sporulated oocysts which can be found in water, soil or vegetables. After ingestion cysts (or oocysts) are disrupted and the bradyzoites (or sporozoites) are released into the intestinal lumen where they rapidly enter cells and multiply as tachyzoites. Immunodeficiency allows reactivated parasites to proliferate and cause severe disease whereas re-infection does not appear to cause clinically apparent disease (Elbez-Rubinstein et al., 2009; Holland et al., 1988b; Luft and Remington, 1992). Genetic examinations revealed that the population structure of T. gondii is mainly clonal. However, analyses in South-America found evidence for the existence of further clonal and non-clonal T. gondii lineages and, in addition, sexual recombinant strains. For many other regions of the world there is only limited or no information available on the genetic composition of the T. gondii population. The genetic diversity between lineages and strains may contribute to differences in virulence and epidemiological pattern of occurrence and there are reports indicating that the clinical pattern of OT might be influenced also by the genotype of the parasite [see Sections 3.1.1 and 3.1.2] (Shobab et al., 2013; Wendte et al., 2011). 1.3. Prevalence of T. gondii infections and ocular toxoplasmosis T. gondii is a widespread parasite that infects almost all species of mammals and birds on all continents. Approximately 25e30% of the human population is infected with T. gondii. However, seroprevalence varies greatly between different countries (from 10 to 80%) and even within countries. Low seroprevalence has been reported from South East Asia, North America (Dubey and Jones, 2008) and Northern Europe (10e30%). Prevalences between 30 and 50% have been reported for Central and Southern Europe, whereas high seroprevalences are observed in Latin America and in tropical African countries (Fig. 3) (Robert-Gangneux and Darde, 2012). In countries with low and moderate seroprevalence, the seropositivity rates increase with age due to the lifelong but relative low risk of infection (Table 1). Interestingly, in countries with high seroprevalence, seropositivity rates plateau at relative young age (e.g. in Brazil at the age of 20e29 years). These differences in seropositivity rates are most probably explained by the different prevalence of Toxoplasma cysts and oocysts in the environment. However, even in countries with very high-seroprevalence some people remain seronegative throughout their life. The prevalence of toxoplasmic retinochoroiditis follows the same geographical pattern. Although congenital infection frequently results in chronic recrudescent retinochoroiditis, most cases of OT are acquired after birth (Talabani et al., 2010). Clinically, OT is the major cause of posterior uveitis in many countries but reliable epidemiological data are rare. In a German tertiary centre, 4.2% of all uveitis patients were accounted to T. gondii (Jakob et al., 2009). Pivetti-Pezzi et al. (1996) reported that 6.63% of uveitis patients were caused by T. gondii in an Italian ophthalmological reference centre. In a retrospective study in USA, OT was diagnosed in 8.4% of 2761 uveitis patients (London et al., 2011). Interestingly, many of these patients had immigrated from Mexico, Central or Southern America to the US further illustrating the high prevalence of OT in these green: <10%.. Pal et al. 1991. (2000) and individual sources: (Asatova et al. Fig. Furthermore. gondii.. Sadaruddin et al. 1998. Simplified world map of global seroprevalence for T.80 M. Life cycle of T. gondii.. 2013.. yellow: 20e40%. blue: 10e20%. Tenter et al. Swai and Schoonman. Sakikawa et al. 1993.. Data combined from Pappas et al. 2012. routes of parasite transmission and pathology after infection [reproduced with permission from (Montoya and Liesenfeld (2004)]. Maenz et al. grey: no data available. 2012. (2009). Note to the reader: In several cases seroprevalences depicted may not be a true representative for an individual country since small regional data sets have been used and extrapolated country wide. samples were frequently drawn from populations strongly biased towards pregnant women. 2009. Ashrafunnessa et al. Kistiah et al. .. Colour code: dark red: >60%. 2. 3. Jacquier et al. / Progress in Retinal and Eye Research 39 (2014) 77e106 Fig. 2012... 1996. Minbaeva et al.. Kamani et al.. Lopes et al. striated areas represent strong regional differences. 2009). 1995. red: 40e60%. 0 84. data were extrapolated from text and Fig.0 Brazild 40. 4.d. 2002). f age group 12e19 years. 2. although OT may also develop in the elderly.0 52. A common feature of these studies was that patients with OT were relatively young (around 20 years).0 10.0 87. Hogan in his very early observations expressed the opinion that the severity of vitreous humour inflammation was unrelated to the size of retinal lesions (Hogan et al. study period 2011. Since inflammatory reactions vary tremendously among patients. 2009). giving rise to the hypothesis that autoimmune mechanisms may contribute to tissue damage. 2002). gondii as infectious aetiology (Goldmann Witmer coefficient> 8). e age group 6e11 years. even when this is the most frequent manifestation of OT. parasites were identified by immuno-histopathology and were surrounded by an inflammatory cell infiltrate in more than 50% of examined eyes (Roberts et al.d. However. own observations]. A e Primary manifestation of a large peripheral retina lesion in a 53-year old male patient. in eyes from foetuses with congenital toxoplasmosis.0 Republic of Koreac n. Partial lesions involving the deep layers of the retina are generally associated with little or no vitreous humour inflammation. 1.541 persons analysed. Age % Seroprevalence U. 1B of the publication.5 2.. g n. 65. 2. . In contrast. it remains speculative whether first manifestations follow a less severe course than recurrent episodes disease episodes. Retinochoroiditis Commonly. acute OT appears as a well-defined focus of retinal necrosis accompanied by a vitreous inflammatory reaction. gondii antigens in the areas of retinal necrosis (Holland et al. there is considerable clinical variation and the diagnosis can be rather cumbersome (Bosch-Driessen et al. p < . Labalette et al. Fundus photography of patients affected by postnatally acquired ocular toxoplasmosis. gondii wanes. 10.1.S. Knowledge of the various presentations of OT is important for the clinician and attention to variation of OT may give some insights into disease mechanisms (Fardeau et al. a retrospective study of 210 patients from seven sites in Europe.. However. 2001). Noteworthy is the observation that T. gondii cysts did not appear as the main focus of inflammatory infiltrates.3 n. 2002. In some specimen cysts have also been detected remote from a scar within the inner retinal layers of unaffected retina without associated inflammation. Frequently. Other factors that may predict the extent of inflammation are currently unknown and require further study. more than 70% of OT patients presenting to an ophthalmologist demonstrate already a combination of an active lesion with a healed retinal scar. / Progress in Retinal and Eye Research 39 (2014) 77e106 Table 1 Age-related seroprevalence anti T.0 9. not determined. 1 of the publication. With the exception of transient inflammatory reactions at the time of T. c (Lim et al. 342 persons analysed in rural Brazil. De Retina section corresponding to panel C as imaged by optical coherence tomography (arrow in panel C indicates scan direction).0 15..2.7 n. 1986). 4C). the size of the retinochoroidal infiltrate might be an obvious factor to be considered.A.. n. 5. 2 of the publication.8f 10. when immunity to T..1. North.9 91. B e Active focal retinitis adjacent to an old scarred lesion in a 22-year old female.0 13. 2002. data were taken from Table 2 of the publication.0 64.8 80. Smith and Cunningham.a 0e 9 10e19 20e29 30e39 40e49 50e59 60e69 >70 All ages 3. A further unexpected finding was that macrophages had phagocytosed part of the photoreceptor outer segments.8 e 81 Netherlandsb 9. Punctate outer retinal toxoplasmosis A combination of parasite and host factors is considered to cause this particular clinical presentation of OT. but early investigations in AIDS patients detected T. 2001).0 10.01) and extra macular located retinal lesions (Dodds et al.d..M.d.. A broad range of changes from low grade retinal infiltration to severe necrotic destruction involving all layers including the outer retina. In many patients the underlying choroid is involved and the term “retinochoroiditis” is appropriate. Histopathology of active OT lesions in humans is rarely available. 15. It is characterised by multifocal. Since the Fig.8 a (Jones et al.6 5.5 7. geographical regions. This may imply that previous peripheral retinitis remained unnoticed in these patients [(Bosch-Driessen et al. indicative of recurrent attacks in satellite positions.0 45. Maenz et al. study period 2004.. Whereas in southern Brazil 17. 5.. Labalette et al. Roberts et al.. gondii infection.0 8. 2007)..d. data were extrapolated from Fig. there is often diffuse inflammation in the neighbouring retinal and choroidal tissue (Fig. data were extrapolated from Fig.1 14. study period 1999e2004.. intraocular inflammation does not occur in the absence of active retinal lesions..114 persons analysed in Seoul. Aqueus humor analysis confirmed T.1. d (Ferreira et al. 2008). n.1.0 76. 2012).. 2002).0 50.0 27. RPE and choroid were reported (Dutton et al. gondii IgG antibodies. C e Follow-up of the same individual with pigmented inactive central lesions 2 years later (patient in panel B). 4B).. 1964). 1992) only 2% of people infected with T.. Recurrent manifestation was observed within 15 months presenting with “clustering” appearance. small lesions that are located in the deep layers of the retina and retinal pigment epithelium (RPE). In the immunocompetent patient these active lesions commonly “heal” within 2e4 months with a hyperpigmented scar as a result of retinal pigment epithelium disruption (Fig. 2002.and South America found that more severe inflammation both in the anterior chamber and vitreous humour was related to larger size (>1 disc area.0 26. b (Hofhuis et al. In addition. Interestingly. 2011) study period 2006e2007.d.d.g n. In addition.0 35. 2003). Essential information on the variable inflammatory response and morphological destruction derived from a murine model of congenital OT.7% had OT (Glasner et al. 1988a. gondii in the United States have had episodes of OT (Holland. 2. acute OT lesions are associated with adjacent old scars. Spectrum of clinical presentations 2..960 persons analysed.3 15. Ocular toxoplasmosis e clinical aspects Necrotising retinochoroiditis is considered as the typical presentation of OT and characteristic to such a degree that often further diagnostic workup is not needed. 5. usually there is no or merely marginal vitreous inflammation. 51 eyes). Parts BeD: a few punctate spots are seen in the vitreous cavity. SAG2. / Progress in Retinal and Eye Research 39 (2014) 77e106 inflammatory process is restricted to the outer layers of the retina.1. Parts bed: abnormalities detected included photoreceptor inner segment-out segment (IS/OS) junction irregularity. indicating that this is an important feature of OT (Eckert et al.. 6) is frequent and may obscure the underlying Fig.3. 1908). 2009. 2012). 1988a. Involvement of the optic nerve might be caused by direct nerve involvement or can be secondary if a retinal lesion is located far from the optic nerve (Jensen. are early findings in OT animal models. Complications Anterior segment involvement presenting as granulomatous “spill over” (Fig. 2. Both. huge outer retinal cystoid space (HORCs) between external limiting membrane (ELM) (white arrowheads) and inner boundary of retinal pigment epithelium (RPE). Saito et al.g..5.g. In almost half of these patients (23 eyes). 2. photoreceptor outer segment (OS) irregularity. 5. 2006). In a series of 926 patients with active OT from Brazil.. Parts b-d represents the magnified (Â4) view of parts B-D. 1985). 1965). fine granular greyewhite lesions will remain. gondii has rarely been identified in ocular tissues other than the retina (Rudich and Bhatnagar. 1993). Photoreceptor layer irregularities can be seen in individuals affected by active OT (Fig. Scleritis T.. In rare cases parasites have been identified in the sclera of AIDS patients affected by extensive retinal inflammation (Schuman et al.4% of all eyes (49 pts. 2007).. 1986). 1988). 15. Since secondary involvement of the choroid is frequent in OT. . 2009).1%) followed by juxtapapillary lesions (18 eyes. Exceptions may occur in immunocompromised hosts. Maenz et al. 5) (unpublished own observation). This observation has led authors to hypothesise about a “protective” immune response in OT. Some patients presented with classical OT lesions in one eye. the patient presented with an area of active retinochoroiditis on the nasal aspect of the optic disc (not visualized here). lesions of the optic nerve were the first ocular manifestation of infection by the parasite.9%). In line with this explanation. A Tcell mediated specific immune response directed against various parasite membrane antigens (e. SAG1) was reported as well as stimulation of CD25þ T-cells (Vallochi et al. More recent imaging technologies confirm these subtle morphological changes e. and/or inner segments. Retinal tissue (black arrowheads) at the lower border of HORCs and above the RPE inner boundary were observed.e.. mixed type (8 eyes. Most patients presenting with punctate outer retinal toxoplasmosis (PORT) were young. Horizontal cross-sectional spectral-domain optical coherence tomography (SD-OCT) images of the right eye of a 54 year-old man presenting with photoreceptor layer irregularities at the fovea. In addition. Frequently. Neuroretinitis There are only few reports of neuroretinitis characterised by optic nerve oedema and hard exudates in a “star pattern”...1.4. optic nerve involvement was rare and seen in only 5. congenitally and postnatally acquired infections were reported to cause PORT and both eyes were involved in approximately one third of patients. 2005b). whereas the fellow eye was affected by PORT (Doft and Gass. by OCT imaging (Goldenberg et al. splinter haemorrhages and papillomacular retinal detachment have been observed (Miserocchi et al. resembling stellate neuroretinitis more commonly seen in Bartonella neuroretinitis (Fish et al.82 M. 35. Following the acute phase. secondary optic neuropathy occurs.7%) and isolated papillitis (3 eyes. 2. The presence of an active distant retinochoroiditis was the most frequent type of lesion and occurred in 22 eyes (43.1. the subjacent area of retinal infection may occasionally result in inflammatory spread to the overlying sclera and present as scleritis. True optic neuritis including necrosis and parasite infiltration has been an early finding in HIV-positive patients and individuals with fulminant congenital OT (Holland et al. corresponding to the disrupted photoreceptor OS.3%). Autoimmunity to retinal antigens has been repeatedly postulated to cause atypical presentations of OT and may also relate to PORT. causing significant visual loss (de Souza and Casella.. demonstrating a selective loss of photoreceptors through secondary autoimmunity (Dutton et al. 2013.. Manschot and Daamen. Of note. 2013). Fujiwara et al. within their first two life decades. intraretinal splits in the outer photoreceptor layer forming a hyporeflective space (i. longitudinal cohort series of 38 newborns with congenital T. 2012). but is very likely more frequent when more subtle techniques like OCT are used (Goldenberg et al.. Common causes were obstructions of the trabecular meshwork with inflammatory cells and cellular debris. 2013). variations in the micro-vascular supply between the peripheral and central retina have been suggested. larger retinal lesions (>1 disc area) and extra-macular location of active lesions were related to increased intraocular inflammation (Dodds et al. Congenital vs. Granulomatous corneal precipitates and elevated intraocular pressure (IOP ¼ 32 mmHg) illustrate the “spill over” effect of a primary retinochoroiditis. 190. retinitis. Vascular complications including retinal vasculitis.. As an explanation for the different anatomic localisations. several experts assumed that the location of lesions may not occur at random. might play a role. The risk for the latter is increased in immunocompromised patients with larger areas of retinal necrosis and higher risk for retinal breaks. In addition. 52% developed central lesions (Phan et al. Macrophages are markedly less frequent in the macula region as compared to the peripheral retina (Yang et al. Higher patient age.M.. / Progress in Retinal and Eye Research 39 (2014) 77e106 83 Fig.. Saito et al. Also the distribution of macrophages. Whereas postnatally acquired infection is considered the more frequent presentation of OT. 2002). central lesions involving the macular region have been considered as highly suspicious for congenital infection (Fig. or optic nerve and has been reported in up to 76% of patients (Melamed et al. Vein as well as artery occlusions have been observed when retinal vessels cross an active OT lesion.. The rate is substantially higher than the expected number if lesions were distributed randomly. there exists no sufficiently validated laboratory test to differentiate the route of infection. The deep retinochoroidal lesion can be clearly demonstrated by horizontal cross-sectional spectral-domain optical coherence tomography (SD-OCT).. severity of anterior segment involvement. Subsequently this may lead to vitreous haemorrhages and acute drop of vision (Kahloun et al.2. A retrospective analysis including 210 OT patients. 6. Differentiation of the macular region is markedly retarded and continues to evolve until the age of four (Yuodelis and Hendrickson. 7.. 2010). 2008). Probably not surprising. reported elevated intraocular pressure in 30% at initial examination (Dodds et al. 1996). 2013. it often remains difficult to distinguish both manifestations based on clinical characteristics only. . In addition. supporting the role vascular growth factors and pro-inflammatory cytokines (Benevento et al. 1986). 2008). arrows a þ b indicate OCT scan direction in B þ C). Alterations of Bruch’s membrane promote development of choroidal neovascular membranes often adjacent to retinal OT lesions. AeC e Fundus photography of a 13-year old patient affected by congenital ocular toxoplasmosis. In particular. when retinal lesions are detected already at birth. gondii infection and ocular involvement. acquired infection Congenital toxoplasmosis with an annual incidence of approx. fovea. 2008). Central vision can be severely impaired if OT lesions involve the maculopapillary bundle. Macula oedema has been detected in approximately 10% of patients. IOP increase and vitreous inflammatory reaction were significantly correlated.000 children remains an underestimated health burden with significant ocular sequelae (Torgerson and Mastroiacovo. 1986). bilateral involvement has been suggested whereas later on acquired infection presents more often with unilateral disease. 2008. Anterior segment involvement of ocular toxoplasmosis in a 46-year old male patient. proliferative vitreoretinopathy and tractional bands may result in secondary vitreous haemorrhage and tractional retinal detachment. This may create a microenvironment that supports the location of ocular lesions. In a well-controlled. 2013). 2008b) supporting earlier observations (Table 2) (Delair et al. However.02) of macular involvement was found during continuous follow up (Faucher et al. Fig. 2010). legal blindness is more frequently seen in congenital OT (Bosch-Driessen et al.. Several case series reported encouraging morphologic and functional improvements following intravitreal injection of antiVEGF agents (Neri et al. 2000). Maenz et al. Predilection of the posterior pole may therefore be related to the earlier development and vascularisation of this anatomical region (Yuodelis and Hendrickson. As another common feature of congenital OT. as an important line of host defence against T. Subsequently.. 2013). 2.. Mets et al... 7). a significantly higher risk (p < ... gondii. Cytokines. 2008). the presence of macular lesions has also been reported in more than a third of patients with documented postnatally acquired infection in southern Brazil (Silveira et al.. Bosch-Driessen et al. 1993). An IL-10 gene polymorphism IL10 -1082 A allele (AA þ AG genotypes) could be associated with the occurrence of OT.. 2009). Interestingly. that outbreaks of acquired OT were also associated with a significant delay (several years) before ocular lesions became active after initial infection (Silveira et al. 1999). 2.. Severity of clinical course. other features commonly thought to be related to congenital infection. However.1.04] (Holland et al. in particular IFN-g and TNF-a. hydrocephalus and T. 1999. the severity of OT can be related to the interaction of parasite and host specific factors. 1995b). gondii infection has been associated with at least five genes at the MHC locus (McLeod et al. a study conducted by Cordeiro and colleagues similarly identified and associated an IL-6 polymorphism (-174 G/C) with the occurrence but not recurrence of OT in Brazilian patients (Cordeiro et al. 2012). congenital OT can not necessarily to be associated with any unique disease characteristics. Genetic host factors 2. Even under the assumption that the prevalence of ocular involvement is higher with congenital infection than with postnatally acquired infection. play an essential role in resistance to T. 2008b.5 0... Wallon et al.5 0. subgroup analysis failed to demonstrate a correlation of allele carriage and severity of OT (based on visual acuity.. However.2 0 (Melamed et al. studies have shown a significant association of the HLADQ3 genotype with disabling congenital toxoplasma infection. (Mets et al.1. More recently. the . host cytokine gene polymorphisms have been the focus of interest since differences depending on ethnicity and geographic distribution have been reported in several infections (Uboldi de Capei et al. 2001). many observations clearly indicate that postnatal acquisition of OT and congenital OT can present with similar clinical findings independent from the mode of infection. experimental data have demonstrated a relevant role for the anti-inflammatory cytokine IL-10 in modulating acute OT.71. Polymorphisms in genes encoding various cytokines have been shown to be connected with susceptibility to parasitic diseases.3.. It has been clearly documented however. Holland et al.. 1989).. the HLA-B62 genotype had also been associated with another critical type of retinitis. 1996)(patients treated) Number of patients Age Mean follow-up Study design Retinochoroiditis Macular involvement (%) Strabismus (%) Microphthalmia (%) Cataract (%) Retinal detachment (%) Irido-cyclitis (%) Nystagmus (%) Ocular globe atrophy (%) 76 0e3 months 5 years Prospective 74 51 34 13 9 9 NI 26 5 (Kodjikian et al. Recent studies have begun to clarify host factors that may have an impact on the severity of human disease and environmental factors that may influence hosteparasite interactions. individuals homozygous for the A allele [þ874T/A] of the IFN-g gene had a higher risk for OT when they possessed the A/A genotype as compared to a negative control group (Albuquerque et al.3. recurrence and bilateral manifestation)..004) related to progressive retinitis. The presence of the HLA-B35 genotype was significantly (p < .. Patient factors related to susceptibility and severity in ocular toxoplasmosis As in many infections. 2004). / Progress in Retinal and Eye Research 39 (2014) 77e106 Table 2 Ocular alterations in congenital toxoplasmosis complied from several sources.9 0. 2010) (80% treated) 44 2 dayse12 months 1 visit only Cross-sectional 66 76 27 12 14 e 14 15 2 Other features commonly related to congenital infection. The fact that severe necrotising retinitis caused by different infectious agents may be associated with the same HLA types suggests a possible immune genetic influence on host responses. The immune system plays a crucial role in both the susceptibility and clinical course of the infection in toxoplasmosis.2. such as delayed occurrence of active clinical disease are also found in postnatally acquired OT. 2003).1. In addition. In addition. These cytokines activate macrophages.. Furthermore. Susceptibility for ocular toxoplasmosis. 2006) (patients treated) 430 6 monthse26 years 12 years Prospective 30 7 5 2 0.. the perception that congenital and postnatally acquired OT vary in clinico-morphological appearance is challenged by a number of observations and in fact might be in part a function of ascertainment bias. It has been clearly documented that outbreaks of acquired toxoplasmosis were associated with ocular involvement and OT developed sometimes after an interval of several years (Silveira et al.. 2013). 2. such as bilateral OT and delayed occurrence of active clinical disease are also found in postnatally acquired infections. recurrence rates in congenital and postnatal OT were reported to be similar (BoschDriessen and Rothova.76... Still. 1989). For example. In an experimental model resistance to otherwise lethal T..3. 2. No such predisposition could be detected in early studies for ocular manifestations (Nussenblatt et al. In addition. 2001)..84 M.3. a major first defence line. The relative risk for macular lesions [RR ¼ 2. more recent investigations identified at least three alleles associated with susceptibility to OT in AIDS patients (Demarco et al.007] was increased in congenital OT in patients that were HLA-B62þ (Meenken et al. p ¼ . Taken together. Earlier studies already established that MHC class I genes and CD8þ lymphocytes determine the critical number of tissue cysts following infection (Brown and McLeod. the “acute retinal necrosis syndrome” [RR ¼ 2. With respect to the human situation. p ¼ . However. 1990). The notion that severe ocular impairment is more often registered in patients with congenital OT is challenged by the observation that such patients can also present with mild ocular disease (Phan et al. Indeed. 2002..006] and bilateral OT [RR ¼ 3. gondii infections.32.1. gondii encephalitis (Mack et al. To investigate potential relationships between HLA types and severity of OT only limited data are available. Maenz et al. 2001). p ¼ . 2002).. Since long term low-dose antimicrobial therapy significantly reduced the risk of recurrent OT. reduction of recurrences is an important treatment goal. a role for TLR9 was detected that may lead to pathologies such as OT (Peixoto-Rangel et al. Other factors that have been considered to influence recurrences are changes in tissue cysts with reduced release of parasites or antigens. information that is lacking in all cited publications. Extrapolation of age related risk would require correlating T..g. indicate an important role of the balance between Th-17 and T-regulatory cells in OT (Sauer et al.. 2010). gondii epidemic outbreaks. de-la-Torre et al.1 years) (Bosch-Driessen et al. 1969.. 2008). Acutely infected individuals without ocular involvement were approx..g. univariate analysis indicated a generally reduced risk of recurrent episodes in the older population. However. However. Subsequently the probability of recurrences will be reduced over time after an active episode. endocrine fluctuations. Previously. The role of IL-17 has been further investigated. e. 2009) involved in autoinflammatory processes (Ogura et al. multivariate analysis including the age of the first active episode. In fact. Unexpectedly. particularly in southern Brazil. Individuals with primary toxoplasmic retinochoroiditis without a pre-existing retinochoroidal lesion were older than those with recurrent OT (BoschDriessen et al. more studies are required to substantiate that genetic risk factors predispose for severe OT. 2009). 1992. size of lesions or antibody levels could be established (Bosch-Driessen et al. Dutra et al. almost 80% of patients were aged 15e45 years (mean age. 1988a). 1995). Patient’s age at the first symptomatic episode of OT is remarkably similar in many studies. the main cellular source of IL-17A was identified as CD4þ CD45ROþ T-betneg IFN-gneg Th-17 cells. Since other confounding factors. congenital infections (vs. 2002. are unlikely to play a role in those cases. 2008). Immunofluorescence images suggested an early IL-17A production by resident retinal cells rather than infiltrating T-cells.1... in the above mentioned Dutch cohort. In addition. while patients whose OT was first diagnosed and revealed recent seroconversion. O’Connor. Not only congenital acquired infection.. based on a questionnaire) were reported (Garweg et al.. the viability of tissue cysts in the retina decreases and they eventually die. Altogether. these results suggest that NOD2 influences the production of IL-17A by CD4þ T-lymphocytes and might contribute to the development of OT.. 2008). given the natural steadily increasing seroconversion over decades. 2005a... older age of patients at first manifestation had an impact on the risk of recurrences. 2004).3. trauma. It has been postulated that recurrences are associated with proliferation of live organisms that emerge from tissue cysts.. Garweg et al. 2002. Friedmann and Knox. this distribution may not truly reflect a particular risk for this age group. Given the risk of a potential blinding condition by repeated exacerbation. the interaction with host factors.. The nucleotide-binding oligomerization domain containing 2 (NOD2) is an intracellular pattern-recognition receptor grouped in the NOD-like receptor family of proteins (Shaw et al. 1969. Of particular interest are reports on T. Over time. Even when a shift towards the importance of parasites genotype currently occurs.. primary lesions (vs.03) increased and presumably related to the waning immune defence in the ageing host (Holland et al. Supported by a small family-based study.. 2001. More recent investigations performed.. Silveira et al.g. none of these putative factors could be substantiated. 2. Ronday et al. 28 years of age.3. as already reported in the brain (Kawanokuchi et al. 2008. Interestingly also. In these patients. Maenz et al. e. Another recent survey of Swiss patients appears to contradict these findings. 1998). If individuals could be identified having a higher risk of recurrences. the authors found an increased IL-17A production in patients with acute OT. 2. Smith and Cunningham. Most notably. since more OT recurrences among younger patients (below age 30.. older age was a major risk factor for OT (Dubey et al. 2009.2. 2012)..9 years. suggest a higher risk for the older aged individuals.. Several European centres reported a mean age of the first symptomatic episode between 25 and 31 years (Bosch-Driessen et al. Toll-like receptors (TLR) are important transmembrane proteins that recognize microbial components and orchestrate an early immune defence leading to the production of proinflammatory cytokines. 2012. 1999). 2002). Patients’ age The impact of patient’s age on several features of OT has been debated for decades. / Progress in Retinal and Eye Research 39 (2014) 77e106 85 relative risk values are low and other confounding factors influencing disease characteristics remain of interest. Portela et al. that the risk of a recurrence appears to be higher during the first year following an active episode of retinochoroiditis (Bosch-Driessen and Rothova. age specific factors seem to be important. local IL-17 production was detected in a rat model of autoimmune uveitis and astrocytes could be identified as a major source (Jia et al. Hovakimyan and Cunningham. However. The relative risk of individuals aged 40þ was significantly (p < . Patient age and recurrence of ocular toxoplasmosis. 1999. it may suggest that there is a relationship between episodes of active disease and relatively young age. Also in other areas of the world. recurrent lesions). the highest rates of OT are found in young adults (Glasner et al. 2009.. gondii seroprevalence for different age groups.M. 1988. but also patients at older age. However. Patients with a first manifestation of OT in connection with serologic evidence of a timely distant acquired infection. e. Canada. may be responsible for this early production of IL-17A. 2001)... Fardeau et al.2. Although the retina remains poorly explored. it has been shown that resident cells. patients age remain of interest. The overall recurrences rate in Europe is up to 80% of all OT patients followed for more than 5 years (Bosch-Driessen et al. In a series from the Netherlands including 274 active OT episodes. Gilbert et al. in COL2A1 encoding type II collagen and purinergic receptor P2X(7) are associated with risk for severe OT (Jamieson et al.. Also in Brazil with its relative high seroprevalence. An array of investigations in Brazil focused on the hypothesis that the host genotype and immune response relates to the severity of OT. This supports the notion that an increased risk of recurrence appears during the first year following active retinochoroiditis.. were substantially older [mean age: 50. 31. both experimentally and clinically. Friedmann and Knox. reducing the pool of cysts from which reactivation can occur. had a mean age of 29. 2011). most notable parasite genetics. 1983). 2002)... postnatally acquired infections). an increased interleukin-17A (IL-17A) production was found in patients with OT. in British Columbia. seem to be at higher risk. 2008. Instead. polymorphisms in the ABCA4 encoding ATP-binding cassette transporter. Studies from the Netherlands indicated. younger patients at risk with macula and . 2008). no association between recurrences and treatment. Interestingly. a critical evaluation of the current literature identifies the more extremes of ages as a risk for OT. 2002.6 years] (Bosch-Driessen et al. such as glial cells and/or astrocytes. Holland et al. 2002). Holland et al. 2002. whereas the mean age of patients with OT was 54 years (Burnett et al. (2013) evaluated the involvement of the NOD2 receptor in susceptibility to OT.. this may lead to a stratified treatment approach. Even when it is difficult to compare clinical studies directly. and transient humoural or cellular immunoreactivity (Garweg et al. 2002. . The prevalence of OT in this population at risk is not known and most data derive from case reports. findings that are supported by early experimental work in primate studies (Holland et al. Atypical presentations include simultaneous multifocal retinitis. Similar problems and atypical clinical presentations of OT can be seen in patients receiving immunosuppressive drug therapy. 2005). 2003). Differential diagnosis In nearly all typical clinical cases of OT T. the clinical course is far more severe. An anterior chamber tap confirmed T. gondii DNA and subsequent steroid treatment improved vision (Sendi et al. First. stage of the parasite and route of infection.. such as the presence of a large active lesion without a scar. with the use of HAART. Indeed. 2004). CMV retinitis). Maenz et al.1] and by laboratory techniques.4. 2013). another route of infection in these patients might be responsibly for the dissemination from non-ocular sites. Ageing is associated with complex changes in both adaptive and innate immune mechanisms that increase the prevalence and severity of many infections in the elderly.. the lack of retinal haemorrhages and retinal lesions with sharply demarcated borders may help to distinguish OT from viral retinitis. unawareness of the risks to acquire OT and non-compliance with HAART was recently reported in more than 30% of these patients. immunodeficiency allows T. toxoplasmic encephalitis became an important cause of morbidity and mortality in these AIDS affected individuals (Snider et al. However. it remains possible that recurrent OT results from repeated infections with more than one type of parasite (Aspinall et al. This might simply be explained by the fact that oocysts containing sporozoites are more resistant to digestion than bradyzoites. This may imply that T. indicating acute acquired OT. Another explanation for recurrent OT could be the reactivation of cysts at distant sites (i.. It has been argued that OT was not caused by reactivation of encysted parasites and ocular disease was more probably the consequence of recurrent parasitaemia. Oct.3. In any case. Often these individuals demonstrate an atypical.2. Whether oocysts cause OT more frequently in humans is difficult to ascertain.4. 2006). given the high seroprevalence rates of T. all components known to be involved in host defence against T.g. However. The impact of the immune system is also emphasized by the observation of a T.. Alternatively. / Progress in Retinal and Eye Research 39 (2014) 77e106 parafoveal lesions might be considered for this approach (Silveira et al. issue 5.. accompanied by large exudative lesions (Vasconcelos-Santos. 2. Xavier et al. Oocysts are more virulent than tissue cysts of the same isolate (Dubey et al. more commonly found in CMV retinitis. 2012 ). gondii-specific IgG serum antibodies are present and indicate past infection (congenital or postnatally-acquired). Commonly however. neuro-toxoplasmosis remains the prevalent cause of neurological disorders in HIV-positive patients leading to severe pathology including lethal consequence (Weiss and Dubey. Whether AIDS patients per se are at higher risk for primary acquired OT is not clearly documented. 1981). following organ or bone marrow transplantation (Chung et al. HAART substantially improves the quality of life and prognosis of HIV-positive persons. 2011). 1988a)...4...1. e. skeletal muscles) and subsequent haematogenous spread to the retina (Silveira et al.. 2012). gondii-specific antibodies nearly excludes the possibility of OT.g. This eventually makes it necessary to combine different serological test systems in those patients with typical ocular manifestation but initially negative IgG test result. 2011. 2002).. active bilateral lesions and extensive areas of retinal necrosis.. natural killer cells.g. 2012). case reports indicate that in extremely rare cases false-negative serological results might occur (Bidgoli et al. Interestingly. a few years later after T. numerous atypical clinical manifestations also exist. Additionally. Serological findings Several diagnostic test systems can be used either for screening purposes or for the discrimination of T. Although the absence of T. However. 24. Even when some clinical features.86 M. in most patients no pre-existing retinal lesions were found (Bosch-Driessen et al. 1988b). For these and other atypical clinical manifestations of OT. gondii serology is helpful for appropriate preventive measures in individuals of high risk for reactivation. IgA. Serological tests for IgM antibodies indicative of primary infection are usually negative (Contini.. 2. Finally.e. Other factors A variety of other factors may influence the susceptibility and severity of OT. Observations of disease outbreaks such as the Atlanta epidemic with 95% disease penetration have also been related to infections with oocysts rather than tissue cysts (Dubey et al. pure clinical diagnosis of toxoplasmic retinochoroiditis may be inconclusive since other types of uveitis may share certain clinical features with OT. 2012) (For more information on immunosenescence the reader is referred to the special issue of Seminars in Immunology. 2. Patient immune status e disease in immunocompromised individuals Early on the AIDS epidemic has shown the tremendous impact of the host immune defence and its relation for severe T. 2009). gondii to proliferate and causes more severe disease. e.4. indicating the need for primary prevention programs (Xavier et al.. and .3. 1983). gondii induced immune recovery uveitis. This is probably supported by the observation that immuno-deficient patients do not always develop recurrent disease. IgG antiT. Until today. 2008). toxoplasmic encephalitis was the initial AIDS-defining illness in up to 33% of all patients (Silva et al. gondii infections. In such cases additional tests for other candidate pathogens need to be conducted (Table 3). 2. gondii-specific IgM. these changes involve lymphocytes. laboratory diagnosis is extremely helpful for determining the aetiology of disease (Vasconcelos-Santos. In animal models disease susceptibility and severity has been altered by the dose of inoculum.. analysis of intraocular fluids is advised (Balansard et al... gondii associated encephalitis was documented also ocular involvement was described (Holland et al. gondii-specific IgG antibodies in the populations of most countries (Gross. determination of this serologic marker is merely considered confirmatory. 2. However. 2002). A HIV positive patient with markedly reduced CD4þ cell count (11/mm3) developed fulminant uveitis when his immune system was recovering following effective HAART treatment. 2002.3. the presentation of post-natally acquired ocular toxoplasmosis may also appear in various clinical aspects. Not unexpectedly. However. 2012). fulminant clinical course of OT and provide a great diagnostic challenge. 2011). gondii serum antibodies were found in up to 95% of AIDS patients with neuro-toxoplasmosis (Mohraz et al. gondii (Solana et al. even when compared to other opportunistic infections of the retina (e. Before the introduction of Highly Active AntiRetroviral Treatment (HAART). 2008).g. Severe OT in elderly patients has also been attributed to alterations in host immunity. 1981). Diagnosis e serology and intraocular investigations The diagnosis of OT can be established clinically [see Section 2. The essential role of the host immune response is underlined by the fact that patients are particularly at risk when CD4þ T-cell numbers are reduced below 200 cells/mm3. vol. 2013). this doesn’t exclude that cysts may have existed in a dormant state and became activated when immune protection was waning. e. and macrophages. respectively (Lynch et al. 1996. In contrast. 2005. the presence of specific IgM and/or IgA antibodies in the serum indicates acute infection. gondii as measured by an ELISA can be present during acute ocular toxoplasmosis and may therefore be useful as a complementary diagnostic marker. gondii makes it necessary to perform laboratory tests which confirm this localised clinical entity.. a peptide microarray using in silico-predicted epitopes recently showed promise to more precisely diagnose ocular toxoplasmosis using serum samples of respective patients (Maksimov et al.. gondii antigens was investigated. IgG3 and IgM antibodies and e although being considered for decades as the golden standard e is now only performed in a few laboratories. 8).. the immunoblot technology allows determination of antigen-specific immuno-reactivity. As mentioned above. 2011. However. others could not confirm the discriminatory power of systemic cellular T-cell responses to soluble T... predominant in myopic females. gondii antigens (Fatoohi et al. VZV) Tuberculosis Sarcoidosis Lues Clinical findings and characteristics 87 Often asymptomatic. Analysing tears from 156 patients with active posterior uveitis revealed a sensitivity and specificity of 66% and 72%. scotoma. In contrast to the ELISA. A retrospective analysis of patients who suffered from active OT from 1995 to 2010 recently revealed significantly higher serum IgG antibody concentrations compared to patients with latent. 2010). 2009). multiple. given the fact that clinical manifestations of acute toxoplasmosis are mostly caused by the highly replicative tachyzoite rather than the dormant bradyzoite/cyst stage of T. skin. When validating serological assays for diagnosis of toxoplasmosis. Preliminary data suggest that lacrimal-specific secretory IgA antibodies against T. However. this technique allows Ig-class discrimination in response to antigen presentation as already demonstrated by Riss et al. small lesions (‘Histo-Spots’). Li et al.. Pfrepper et al. IgM. In most cases.. frequently progression with new lesions and increasing vitreous involvement Often acute onset of symptoms (decreased vision. 1966). often anterior segment involvement Symptoms depending on localisation. gondii stage-specific antigens does not seem to allow a clear discrimination between patients with OT and latent toxoplasmosis as has been shown in our preliminary analysis using a recombinant line blot assay (Fig. initial: in peripheral retina.. several assays using whole parasite cell lysates are commercially available.. 2012. was significantly increased in patients with laboratory-confirmed or clinically suspected OT (Chumpitazi et al. but becoming more confluent over time. atypical manifestations. e. the enzyme-linked fluorescence assay (ELFA). one has to take also into account the antigen(s) utilized by the given test. 1998. Besides serum. 2011). photopsia. (bilateral) choroidal lesions. 2010). unilateral rapidly progressing necrotising retinitis. given the fact that OT is one possible clinical manifestation of systemic infection with T. 8). such as active lesions without scars are indicative of acute acquired OT. patient tears have recently caught attention as specimen for discriminating between systemic and ocular toxoplasmosis. no vitreous involvement. Using a line blot as a further development of the immunoblot technology has the advantage to simultaneously analyse antigen-specific immuno-reactivity against stage-specific parasite antigens (Fig. 2011. Wu et al. respectively with positive and negative predictive values of 72% and 65%. and IgA antibodies are the immunosorbent-agglutination assay (ISAGA). gondii is not necessary in adolescent and adult patients with typical manifestations of OT. Golkar et al. Maenz et al. . bilateral active retina lesions. and the immunoblot. Whereas Yamamoto et al.. Test formats that discriminate between IgG. 2008. Here.. especially those with vasculitis. gondii-specific serological assays several immunological approaches for identifying systemic biomarkers indicative of OT have been published and await further confirmation. the presence of IgM and IgA serum antibodies confirm acute infection. involvement of other organs (lung.g. However. / Progress in Retinal and Eye Research 39 (2014) 77e106 Table 3 Differential diagnoses of toxoplasmic retinochoroiditis. predominantly mid-peripheral retina. gondii tachyzoite antigen than asymptomatic persons. sharply bordered. as “acute syphilitic posterior placoid chorioretinopathy” it is often multifocal with vitreous inflammation IgG antibodies.. several approaches have recently utilized recombinant antigens in serological assays for differentiating between acute and latent toxoplasmosis (Beghetto et al. Amongst these. the ELISA is most often used given its advantage of automation. laboratory findings essential (PDD-. usually indicating persisting infection.. 2012). respectively. 2006. Pietkiewicz et al. IgG antibody level against heat shock protein (HSP) 70. small central lesions (100e300 um). Quantiferon test) Often multiple granulomatous changes. determination of serum antibodies which are directed against T. Since treatment resulted in a significant reduction of this chemokine. Marcolino et al. As retinitis it can be patchy early. gondii. Of these... One of these.1. inactive toxoplasmosis or controls (Papadia et al. Differential diagnosis Multifocal Choroiditis PIC (Punctate Inner Choroidopathy) POHS (‘Histoplasmosis’) Acute retina necrosis syndrome (Herpes-simplex-Virus. Holec-Gasior et al.. 2007). it allows the laboratory discrimination between congenital and acute acquired infection in most cases: congenitally acquired infection is likely when high-avidity IgG antibodies are present and IgM antibodies can not be detected. 2000. serum versus aqueous humour. often: CNV Often asymptomatic. 2000). 2007). Even today. whereas high-avidity IgG antibodies can be detected if the infection has been acquired more than four months before (Cozon et al. However. (1995). often no pulmonary involvement. a further development of this cellular immunology-based approach is the diagnosis of congenital toxoplasmosis by using a whole-blood gamma interferon release assay. Although determination of serum antibodies against T. it was suggested to be a useful marker for patient follow-up (Goncalves et al.. 2009).. Conflicting results were achieved when the cellular immune response against T. The Sabin-Feldman dye test measures IgG1. 2006). the tachyzoite major surface antigen SAG-1 is the most frequently used recombinant antigen that is applied in commercially available ELISA assays (Harning et al. which in principle might as well be adapted to OT (Chapey et al. Maximum titres are reached at six to eight weeks after infection and later persist lifelong at low levels. Concomitantly. which is extremely helpful when analysing different anatomical compartments.M. More frequently in use are immunofluorescence assays which are measuring immunoglobulins of all classes and mimic the titre kinetics found by the dye test (Walton et al. liver) “The great imitator” presents with variable morphological changes.. In addition to T. haemorrhagic lesions. initial: multiple. often multiple choroidal infiltrates. the enzyme-linked immunosorbent assay (ELISA). peripheral. (2000) found that patients with ocular lesions have higher IL-1 and TNF-a responses toward soluble T. Hruzik et al. Increased serum levels of the chemokine CXCL8 were identified in patients with active OT. frequently: CNV Acute onset. immunoblotting allows the determination of T. Comparing laboratory methods on intraocular specimen. Talabani et al. and IgG (G) humoural immune responses of three patients with OT against eight recombinant Toxoplasma antigens (A-H on the right). neither the PCR protocols nor the parasite DNA fragment to be amplified have been standardised. 1953a. However. Villard et al. Despite the fact that OT continues to be a very common and sight-threatening cause of infectious posterior uveitis. The diagnosis is based on i) the determination of intraocular production of T. 8.5. in contrast to PCR which is positive within the first days of clinical onset of ocular lesions.g. Furthermore. There are few studies which compared treatment approaches allowing us to judge which treatment might be best. 1992). GWC. the interval between onset of clinical manifestations and aqueous humour analysis seems to strongly influence the detection of intraocular antibody synthesis (De Groot-Mijnes et al.. 2012). 2011. when immunoblotting. Talabani et al. gondii B1 gene was positive in 11 out of 13 patients with suspected OT. Initially performed qualitative multiplex PCR on the T. which imply that more complex and incompletely understood factors influence the outcome of this detection method (Garweg et al. effectively avoiding immunosurveillance by the host.. . gondii infection is a self-limited (asymptomatic) disease that has been considered to need no treatment. 2. ii) cysts are impenetrable to host enzymes and there are no drugs that can eliminate latent cysts from e.. While specificity of such assays is reported to be very high. 1954).88 M. Representative line blot assay analysing systemic IgA (A). 2005b). 2003). which is discussed in the next section. 2005. 2007). Garweg et al. resulting in a low coefficient (Vasconcelos-Santos. In this regard it is important to note that leakage of antibodies might occur when the blood-ocular barrier is disrupted. Definite laboratory confirmation of OT is achieved by the detection of T.. and real-time PCR were compared for diagnosing OT in 54 patients with atypical uveitis.3. Errera et al. 2006. Maenz et al.. retinal tissue. based on parasite characteristics such as: i) the ability of the parasite to form cysts as a very successful strategy for its survival. the combination of pyrimethamine... Detection of T. Intraocular antibody synthesis can be identified by parasite antigens that are immuno-reactive when aqueous humour is applied to the immunoblot but remain un-reactive with serum from the identical patient. gondii antigen-specific antibodies. moleculargenetic detection methods based on polymerase chain reaction (PCR) techniques have been studied and used successfully (Contini et al. Westeneng et al. However..g. e. The concentration of respective antibodies is demonstrated by the presence and intensities of blue lines. sulfadiazine and corticosteroids has remained as the “classical triple therapy”. In many patients T. 2009). 2011. gondii DNA in aqueous humour or vitreous fluid by PCR. 1993.. Treatment goals and general considerations For more than 50 years no substantial changes in the treatment of OT have occurred. / Progress in Retinal and Eye Research 39 (2014) 77e106 Fig. 2008). Bou et al. gondiispecific antibodies and ii) the detection of parasite DNA. Importantly. which is based on the comparison of the T. As mentioned above. a combination of all three methods was 85% sensitive as compared to 80% sensitivity for combining PCR and GWC and 70% sensitivity for combining immunoblotting and GWC (Fekkar et al. 2006). Analysis of intraocular specimen Laboratory assays using intraocular specimen are extremely helpful for the definite diagnosis of OT. gondii DNA in ten of these patients. 1999. production and may result in false-negatives (Errera et al. Corollary to serological and immunological test. Garweg et al. 1996). which interfere with parasite replication.. Since then.1. IgM (M).. Treatment 2. Intraocular antibody synthesis is determined by the GoldmannWitmer coefficient (GWC). individual differences in the time interval between clinical symptoms and activation of local antibody production might make it difficult to identify local antibody 2. Subsequently performed quantitative real-time PCR showed high copy numbers of T. Already in the early 1950s the synergistic action of pyrimethamine and sulfonamides. 2008. Garweg and Boehnke. especially when atypical ocular manifestations hinder the clinical diagnosis. observations for a population specific immune response have been made. A two-step PCR system proved to be a valuable tool for determining active versus inactive OT.. Ho-Yen et al. treatment remains highly controversial. Localised intraocular antibody synthesis is likely when the coefficient is high. 2011. to date.5. from a clinical point of view many questions remain open: 1. However.... the three real-time PCR-negative patients proved to have only scar lesions (Sugita et al. Thus. This is related to a number of factors. realtime PCR seems to have an inferior sensitivity compared to GWC (Errera et al. 2.4. In addition. was demonstrated (Eyles and Coleman. 2000.. 2011). b). One key challenge in toxoplasmosis is to develop a drug that is able to eliminate the cyst stage of the parasite and thus efficiently impairs relapse of the disease. gondii DNA is much more relevant in aqueous humour samples.. sensitivity may vary considerably (Aouizerate et al. gondii-specific antibodies in the aqueous humour and in the serum in relation to the globulin titres in the same fluids (Goldmann and Witmer.. confirming OT by relying solely on detection of intraocular antibody production seems to be sub-optimal but a combination of techniques improves the diagnostic yield (Fekkar et al. 2009. randomised clinical studies. iv) efficacious against both bradyzoites and tachyzoites. It is probable that differences in clinical presentation and different strains of the parasite may relate to different treatment approaches. 2002. subsequent clinical experience showed no effect on disease recurrence (Lakhanpal et al. In addition. Systemic treatment e the “classical” drug combination. To have biological function. 2013).. there were problems with the design. Small scale uncontrolled studies showed apparently accelerated rates of resolution and improved acuities in patients on the combination (Opremcak et al. 2. Furthermore. and v) well tolerated without adverse effects (Garweg and Stanford. A nonrandomized treatment study including 149 patients treated with pyrimethamine/sulfadiazine resulted in a reduced lesion size when the size of active retinal inflammatory lesions was compared to the resulting retinochoroidal scars (Rothova et al. however. Clindamycin was a very promising substance when introduced in the 1980s (Tabbara and O’Connor. iv) retinochoroiditis in immunosuppressed individuals (since untreated patients very likely develop fulminant. The detailed pharmacological mechanisms of action have been recently reviewed by Kortagere and McFadden (Kortagere.. 2012.5. as secondary outcome measures were used: a) duration and severity of symptoms. significant uncertainty with regard to proper medication by experts in the field.. Clinical studies 2. others will treat all lesions independent on its location (Basu et al. 1975). In most patients the treatment course needs to be continued for at least 4e6 weeks. Only one study observing individuals infected with probably more aggressive South American strains of T. there is observational evidence of treatment effects. progressive lesions).. Whereas some ophthalmologists will only care for sight threatening lesions.. 2008). They identified only three prospective. could not be demonstrated.3. 2002) determined the effect of long-term (20 months) prophylactic trimethoprim/sulfamexacol treatment compared with no treatment in patients with chronic relapsing OT. Alternative routes of medical treatment e intravitreal drug delivery. gondii demonstrated that long-term antibiotics (14 months) reduced the number of recurrences...M.. the impact on quality of life and burden of disease in affected individuals remains an important question. 2011. 2011. 2001). Holland and Lewis. 2001... Still. indicating that at least nine separate drugs in even more combinations are currently used in daily practice (Basu et al. 1983). No consistent outcome measures have been established so far..g. this compound has to cross several layers of membranes. uveitis specialists appear to be more likely to treat patients with OT as compared to a decade earlier (Holland and Lewis. a number of alternatives to the combination of sulfadiazine and syrimethamine have been applied to OT patients. In all studies. 5. As in other parasitic diseases. There appears also an increasing use of the trimethoprim/sulphamethoxazole combination.3. Recent treatment attempts focused on the use intravitreal drug delivery (Hazirolan and Pleyer. There was a lack of evidence in all studies that antibiotics (shortor long-term) prevented vision loss. 1992).. In addition. using eight weeks of pyrimethamine/trisulfapyrimidine versus placebo in patients with acute toxoplasma retinochoroiditis or four weeks of pyrimethamine compared with placebo in patients with acute uveitis due to any cause. These positive features were supported by findings in animal models. 2010) were introduced into clinical use but have not gained widespread acceptance. 4. 1973).1.2. In all studies side effects of any used antibiotics were minimal regarding decreased white blood cells. others focused on recurrence of retinochoroiditis or the size of the lesion. Interestingly. 2013).3.5. 2013.3. however.. the plasma membrane. This is reflected by several surveys of uveitis specialists in the USA.5. making it very difficult to set up well designed. offering a better option for compliance as does the standard combination of a dihydrofolate reductase inhibitor and sulphonamide. Torun et al. e. Current treatment indications Despite limited evidence of treatment effects. rashes and other allergic reactions. loss of appetite. Current treatment approaches are based on agents that affect the parasite at different pathways. Finally. and. / Progress in Retinal and Eye Research 39 (2014) 77e106 89 3.5. iii) large lesions >2 optic disc diameter. ii) lesions in close proximity to the optic disc (since substantial visual field defects may result). b) ocular discomfort due to acute retinochoroiditis (any measure). Although it has been difficult to demonstrate that treatment alters the natural history of active OT. Several surveys of uveitis specialists indicate that even experts differ in their therapeutic approaches. The clinical course of OT varies extremely. ii) risk of one or more recurrences of retinochoroiditis at the end of follow up (of any duration). 2010). no treatment or placebo. 2.5.. performance and analyses. 1993). Torun et al. 6. 2. McFadden et al. 2008).. Interestingly. such as improvement in visual acuity or reduction in the duration of disease. Subsequently. A recent meta-analysis reviewed all randomized trials on the treatment of human toxoplasmosis (Rajapakse et al. placebo-controlled clinical trials using systemic antibiotics for OT.. 2002. it was well tolerated as long term prophylaxis over 14 months in high risk patients (Silveira et al. all patients receiving antibiotic treatment were also on corticosteroids.. However. d) adverse events (any mentioned). randomised. iii) able to penetrate cyst walls. 2002). most probably intracellularly the membrane of a particular organelle. Lasave et al.. c) size of lesion at the end of follow up (any measure). Winterhalter et al. which is likely to cause side effects. 1998) and atovaquone (Pearson et al. Common clinical indications include: i) lesions within the vascular arcades (since they threaten central vision). azithromycin (Rothova et al. which may have affected the results. Maenz et al. Two primary outcome measures were defined: i) visual acuity or change in visual acuity at least three months following treatment. 2002). 2.2. including inhibitors of nucleotide metabolism and translation and inhibitors of the electron transport. there are major hurdles to overcome before an active therapeutic agent might be approved. 1999. The ideal agent to treat OT should be: i) parasitocidal. Whereas some investigators used duration of symptoms and signs of acute inflammation as criteria. Holland and Lewis. In the late 1990s. two of these studies were conducted almost 40 years ago. The review included 3 studies on OT with a total of 173 participants of any age treated with antibiotics. 7. Other potential benefits of this treatment.3. ii) concentrated in the eye. Only the third study (Silveira et al. Germany and India. since the drug reduced the number of tissue cysts (McMaster et al. parasite membrane. Kishore et al. Since high concentrations of therapeutic agents can be delivered to the vitreous . the conclusion for the clinician to leave OT patients without intervention seems not to be justified. Systemic treatment e other antibiotics. 2012). The second study was unable to demonstrate that short-term treatment with antibiotics altered the clinical course in any respect. 1980) because it appeared to concentrate in ocular tissues and was considered to penetrate tissue cyst walls (Tabbara and O’Connor. clindamycin has been applied as intravitreal injection (Baharivand et al. There remains. Since active intraocular inflammation always carries a risk of complications likewise no other intraocular surgery is advised. 1988a).5 mg/0. multi-centric interventional case series. 2013).1 ml) every 4 weeks (during pregnancy). and systemic undesired effects can be avoided. This contrasts markedly with previous observations for children left untreated or those treated for one month only (82% retinal lesions). early intervention. 1995a).g.. 2010. These observations suggest that parasite proliferation.4. is the major cause of tissue damage in these individuals. Guerina. Whereas routine screening programs during pregnancy have been implemented in several parts of Europe. There remains significant uncertainty with regard to proper approach by experts in the field... Spalter et al. A recent systematic review did not identify evidence from randomized controlled trials for the role of corticosteroids in the management of OT (Jasper et al. 1999.. corticosteroid therapy is probably not necessary to control OT in immune compromised individuals. Meenken et al. when (early versus late in the course of the infection). it is strongly agreed upon that corticosteroid therapy without concurrent use of antimicrobial agents can lead to severe retina destruction and large lesions (Garweg and Stanford.. neonatal screening and prenatal screening with monthly or 3-monthly re-testing schedules (Garcia-Meric et al. foetal infection occurs at up to 65e70% and results in significant child morbidity with ocular lesions as the most frequent manifestation (Dunn et al. e.1 ml) and dexamethasone (400 mg/0. Gilbert et al. Therefore prevention and treatment of congenital toxoplasmosis remains an important issue. The global burden of congenital toxoplasmosis is estimated as many as 190. 2011. Reasons for these different approaches have been related to the questionable benefit of early diagnosis and intervention since well controlled studies are lacking and difficult to perform (Freeman et al. Maenz et al. 2008. retrospective. Still.4. 2011. confirming that long-term follow-up is important in assessing treatment during childhood (Phan et al.5. In most European centres.. 2010).90 M... 2010). 2006). Despite the obvious need to address this challenge. concluded that only weak evidence exists for an association between early treatment and reduced risk of congenital toxoplasmosis (Thiébaut et al.. Recent observations confirm that it seems likely that more prompt diagnosis and treatment will result in better outcomes of congenital toxoplasmosis. Interestingly. 2013). 2007). Torun et al. In a non-comparative.000 children per year (CI 95%) (Torgerson and Mastroiacovo. there is still no consensus regarding the choice of antiparasitic agent. A meta-analysis investigating these different data in 2007.. 2011). 2013).5. an ideal head-to-head therapy study will not only be performed with or without steroids. Also recommendations for treatment differ in countries where prenatal screening is performed... Management of congenital ocular toxoplasmosis. but many also consider the underlying parasite types. As in many other ocular infections. Taken together. 1981. at which dosage and duration of corticosteroid administration remain unanswered. Therefore. the number of children subsequently followed up to adolescence is relatively low and larger numbers of such teens will be needed to determine whether this early trend of decreased incidence is sustained. Holland and Lewis. Laser treatment has now been abandoned.4. Congenital OT is recognised as a major cause of child morbidity and mortality. 2008a). Surgical options. Argon laser photocoagulation has been applied with the intention to directly disrupt the organism or to reduce recurrence by surrounding old OT lesions with laser spots (Rodriguez. Since the effect of medical treatment is uncertain. New central chorioretinal lesions have been uncommon in children with congenital toxoplasmosis who are treated during their first year of life (Phan et al... On the contrary. It is likely that the inflammatory response differs not only among various groups of patients but might also be related to the phenotype of the infecting parasite. Gilbert and Dezateux. Interestingly.5. 2013. indicating that at least nine separate drugs in even more combinations are currently used in daily practice (Basu et al. This is reflected by several surveys of uveitis specialists in the US. Therefore the need for large randomised . more than 40% of untreated children presented new chorioretinal lesions when they were 10 years or older. 1994.. However. 1993). In particular. Therefore.. 2. treatment practices in OT are highly diverse. In a prospective randomized study comparing intravitreal clindamycin with 6 weeks of systemic clindamycin treatment they appeared similarly effective independent from route of administration (Soheilian et al. spiramycin remains standard treatment and is immediately applied after diagnosis of maternal infection to prevent placental transmission followed by pyrimethamine/sulphonamide as soon as a foetal infection is confirmed in order to treat the foetus directly (Gilbert et al. twelve patients with active OT involving the posterior pole that were either intolerant to or contraindicated to oral medication. 2011). 2008). During follow up (24 months) resolution of OT was achieved in all cases and most eyes (83%) improved. Germany and India. 1986.. rather than inflammation. Contrary. worldwide remarkable differences exist on effective screening and subsequent treatment strategies. 1966). 2008). 2008. other treatment strategies rely initially on pyrimethamine/sulphonamide that will be changed to spiramycin if foetal diagnosis is negative (Gilbert et al. early observations of histopathologic specimen of eyes from immunocompromised patients with OT showed no inflammatory cells in infected tissue (Holland et al. Kodjikian et al.... by the use of corticosteroids is often beneficial to reduce tissue damage. surgical options have been considered for the treatment of OT. 2008b).5. 2006.2. Important questions. Paquet and Yudin.4. Current policies include no screening... e. 80%) of placenta infection (Couvreur et al. in most other countries only postnatal symptomatic children are detected. 2006). the host immune response may have detrimental effects. suffer from eye lesions by the time they reach their teenage years (Koppe et al. and generally the maternal disease goes unnoticed.. Unfortunately.g. Alternative treatment approaches 2. Interestingly however. 2008. gondii in the blood stream as compared to intra-ocular parasites remains speculative. However. whereas 2 eyes (20%) remained unchanged. received intravitreal injections of clindamycin (1. No ocular or systemic adverse events were reported and furthermore no recurrences during 24 months of follow-up were observed (Lasave et al. 1976). Therefore.. 2008). Stanford et al. It has been realised that approximately 80% of children with congenital toxoplasmosis who were left untreated or treated one month postpartum. 2002. Jia et al. neither direct destruction of the organisms nor reduced reactivation of tissue cysts could be achieved even if the parasite was confirmed to be heat sensitive. it has been demonstrated by several studies that treatment with spiramycin resulted in a significantly reduced rate (95% vs. / Progress in Retinal and Eye Research 39 (2014) 77e106 cavity and adjacent retina. Vertical transmission of toxoplasmosis occurs during primary infection in pregnant women (more rarely during secondary infections). The role of corticosteroids. O’Connor and Frenkel. 2. a stronger regression of lesion size has been demonstrated following systemic treatment as compared to IVI (Soheilian et al.1. 2. Melamed et al. This led to a 50% reduced incidence and lower severity of disease at birth of infected infants as compared to untreated individuals (Kieffer et al. Whether this observation can be explained by a higher susceptibility of T..3. Future therapies Since T. Such a decline in seroprevalence has also observed in other European countries. In addition. 2013). Still studies are awaited to evaluate TgCDPK1 inhibitors to demonstrate therapeutic proof in experimental parasitic models. Diverse methods have been used to rationally screen and design new potential agents. gondii. The Netherlands (35. The identification of serological markers for oocyst infection may enable future studies to solve this question (Boyer et al. gondii in domestic cats is 30e40% (Elmore et al. 2003). closely related agents such as Artimiside and Artemisone. Parasitological considerations 3. Several studies analysed risk factors for human infection. demonstrated better in vitro activity and controlled parasite replication in vivo (Dunay et al. In addition. gondii in brain tissue of seropositive patients are lacking.5% in 2006) (Hofhuis et al. gondii is closely related to other protozoan parasites in the phylum Apicomplexa such as Plasmodium. These processes are thought to be largely controlled by T. animal friendly and organic outdoor production of meat increases the risk for exposure of livestock to contaminated environment (Tenter et al. Penetration of the host cell is depending on oscillating calcium levels providing motility. gondii calcium-dependent protein kinases (TgCDPKs). 18. it is believed that seropositivity in humans is equivalent to parasite persistence. Since T. which may contaminate water with oocysts. the cause of malaria. 2011). a single cat can pass more than 100 million non-sporulated oocysts. consumption behaviour of humans and the socio-economic status largely determine the risk of infection in humans (Robert-Gangneux and Darde. One of these compounds is Artemisinin. Immediately upon cell entry. These include ligand-based and structure-based methods.. 2011).1. 3.. Of note. 2010) and hold promise as future therapeutic candidates. But more recently T. gondii (Hencken et al. rodents and cats (Kijlstra and Jongert.1. gondii-seropositive AIDS patients.1. the proportions of seropositive pregnant women were 80% in the 1960s. Since larger autopsy studies analysing persistence of T. the quality of water plays another important role in human infection with oocysts. oxadiazole and carboxamide derivatives of Artemisinin are also highly selective and potent inhibitors of T. 2007). The relative importance of cyst versus oocyst infection is unknown and risk factor studies could not clarify the route of infection in a substantial number of cases. especially in countries with a humid climate and high numbers of cats. parasitology and neuro-immunology of Toxoplasma gondii 3. In general. gliding motility and exocytosis of T. gondii as an intracellular parasite requires invasion of mammalian host cells to proliferate..g.. Seroprevalence in humans.. increased feeding of cats with sterilised food. 3.5. Route of infection. Interestingly. Noteworthy. primary infected cats shed oocyst for 1e2 weeks.. In general.. e. gondii infected and invertebrates such as mussels are frequently contaminated with T.. 2006). demonstrated promising effects in vitro against T. They contain specific binding sites that are more commonly found in plants than in mammalians.2% in 1996. great hope is based on progress in treating these important diseases. On the other hand survival of sporulated oocysts in the environment is favoured by humidity and under optimal conditions sporulated oocysts may remain infective for more than 1 year.1. gondii to humans is the number of infected felids and resulting oocyst prevalence in the environment. These studies identified several specific risk factors for oocyst infection including: playing in sand boxes and school playground (dos Santos et al. gondii from egress from infected cells (Nagamune et al. gondii cysts at autopsy of a patient who died from an unrelated disease (Pusch et al.1. Intracellular calcium has already long been associated with these key characteristics (Lovett and Sibley.1. 2010). 66% in the 1980s. / Progress in Retinal and Eye Research 39 (2014) 77e106 91 controlled clinical trials still seems necessary to provide valid evidence of the potential benefit of prenatal treatment.. 2. environmental and parasite related factors contributing to infection and disease An important factor for the transmission of T. TgCDPK1 represent a promising drug target for the development of new anti-parasitic agents. In sharp contrast. 2011. 2009). Seroprevalence have declined in countries which increased their hygiene standard. marine mammals including sea otters and dolphins are frequently T. insufficient . 2000). Oocysts become infective after a phase of maturation (also called sporulation) which is favoured by warm temperatures. Seropositivity rates in wild felids are in general very high and may be close to 100%. feeding on sterilised food and keeping stables free of birds. whereas the global seroprevalence for T. This assumption is strongly supported by the high risk of reactivation of Toxoplasma encephalitis (TE) in T. in which e. gondii calcium dependent protein kinases became an interesting therapeutic target (Johnson et al... Within ten days after oral ingestion of cysts. 2009). The prevalence of T. contact to soil and gardening without gloves (Cook et al. especially in the brain. livestock and cats in combination with hygiene standards including water hygiene. Use (particularly drinking) of unfiltered surface water bears a high risk of infection.5. 2012). which become infective within 1e5 days after sporulation and remain viable for several months. 2000).1. humans may become infected by cysts and. only one single publication reported incidental detection of intracerebral T. Remarkably. small-molecule inhibitors could be detected. Ca2þ oscillations are reduced thus preventing T. it still remains to be determined to which extent seropositivity correlates with parasite persistence in the brain and eye. In France. Other important questions such as parasite and host specific factors and their potential effect on clinical outcome are of outmost interest (Carneiro et al.. 1997. kept livestock more indoor. Risk factors for infection. seroprevalence in 12e49 years old persons dropped from 14% in 1988e1994 to 9% in 1999e2004 (Jones et al. 2010). gondii. 2012). gondii oocysts with prevalences ranging from 45 to 100% (Jones and Dubey. Epidemiology.2. Also in the US. For instance.. Other. Maenz et al. 2003). 3. contact with contaminated water (Bahia-Oliveira et al. Another line of interest is focussing on enzyme targets (Ojo et al. Ca2þ levels are essential for the biology of the parasite. 2010).. the prevalence of T. 54% in 1995 and 44% in 2003 (Villena et al. gondii in livestock is dependent on various factors and can be reduced by keeping livestock indoor. and consumed less raw meat over the years. gondii cysts in livestock and the consumption of raw meat are major factors influencing the rate of human infections with T. owning of cats. Hill et al. protein kinases are involved in calciumregulated biological processes.1. This might be one reason why seroprevalence in humans is higher in humid tropical as compared to dry climate. Therefore blocking of these protein kinases is considered safe without untowarded effects on human host cells. 2010). 2009)... These marine species become infected by oocysts shed by wild and domestic felids through contaminated water with access to marine ecosystems. The prevalence of infection in wildlife animals. de Moura et al..M. 2008). 2010). Contaminated water has been reported to be a source of small epidemics of OT (Bowie et al.g. gondii but it failed to be effective in an experimental animal model. thus.. such as host cell invasion.. Further common risk factors for cyst and oocyst infection are not washing knives after they have been used to cut raw meet. 8. In addition. 2003). 2011). An experimental sexual cross between members of the nonvirulent Type II and III rendered an F1 progeny highly virulent for mice (Grigg et al. Sheep and pigs are the dominant sources for T.. 2010). transplantation of cornea has not been reported to be a risk for cyst transmission further illustrating that the parasite persists in the retina but not in cornea. infection with tachyzoites is only relevant in congenital toxoplasmosis. 2011.. A well known risk factor for recurrent toxoplasmosis is an acquired immunodeficiency of chronically infected patients.000 births in Brazil (Neto et al. 1990). In contrast to North-America and Europe. although the incidence of cerebral toxoplasmosis dramatically declines in case of appropriate highly active antiretroviral treatment (Montoya and Liesenfeld.. Interestingly. presence of livestock animals.. Clinically.000 births in France and similarly 1 per 3. The course of disease is influenced by the immune status of the host and presumably the genotype of the parasite. 2006). 1996).2. ROP16) [summarised in Dubremetz and Lebrun (2012). There is an ongoing discussion whether the severity of human disease including OT is indeed influenced by genotypic differences of infecting parasites. II and III (or haplogroups 1. 2010).e. ROP5 5. gondii (range from 2 to 90%). 2008).. which have contaminated vegetables and other food. a high genetic diversity of T.. 2000. The seroprevalence in sheep. oocysts remain infective for long time and are not reliably destroyed by freezing and moderate temperatures. Walzer and Boyle. 2006. Recently. domestic cats. These three lineages show only a very limited genetic diversity between each other ranging at the nucleotide level from 0.1. It is hypothesized that T. vegetable. 2002. Identified risk factors for infection with tissue cysts include consumption of undercooked meat. are at risk to develop active OT (Montoya and Remington.. This estimated point of time coincidences with the time humans started agriculture and domesticated animals including e.. chemical and physical treatments including chlorination and ozone treatment (Dumetre et al. Only cooking (>55 C) but not freezing or disinfection reliably destroys sporulated oocysts.... gondii would be expected. 2010).. Freezing at À7 C is not sufficient for inactivation of cysts but deep freezing below À12 C for at least 3 days results in killing of cysts (Kotula et al.. 2012). Su et al. ii) not feeding with raw meat. The risk of foetal infection is inversely correlated with the duration of pregnancy. 2008)... If a sexual cross between lineages can dramatically alter the virulence . these temperatures may not be reached in thick slices of meat. since seroprevalence rates vary between animal species and from country to country. 2.. Kapperud et al.3 per 10. 2000). In North America. 2011b). who also may suffer from impaired immunity. cysts are present in the donor organ. In water. II. pigs and cats (Diamond. 1971). 1991). Garweg et al. Primary infection of pregnant women may result in infection and subsequent infection of the foetus.g. and may cause toxoplasmosis in a seronegative recipient. gondii are highly virulent in mice. This seems to be particularly true for OT as discussed in the following chapter. 2005a)..e.. and also under these natural conditions progeny with various combinations of type II and type III alleles arose and showed differences in virulence for mice (Herrmann et al. and iii) removal of cat faeces before oocyst sporulation. Three clonal lineages occurring in North-America and Europe show strong differences regarding the virulence in laboratory mice (Sibley and Boothroyd. 2008) and leukocyte transfusion (Siegel et al. 2007. The risk of human infection by cats can be further reduced by i) keeping domestic cats indoor to prevent infection by oral ingestion of rodents and birds.. Infection with tissue cysts may also occur following solid organ transplantation (Derouin and Pelloux. seroprevalence for sheep increases from approximately 20% for lambs to 75% in adults (Halos et al. 2008). Finally. Forward genetic analyses revealed that these differences in virulence have a genetic basis and could be linked to certain alleles in loci coding for rhoptry proteins (ROP 18. 10) showing various degrees of clonality (Khan et al. 3. Tenter et al. Mercier et al. Maenz et al. Rosenthal. and III have unique features supporting their expansion in an environment associated with human agricultural and livestock-breeding activities (i. Due to its occurrence under various environmental conditions world-wide and its adaption to various intermediate and definitive host species a high genetic diversity of T.. 6. In Europe. or more rarely in the context of solid organ transplantation (Derouin and Pelloux. 1996).. Although cattle are frequently seropositive for T. patients treated with immunosuppressive drugs and the elderly. Heating (>67 C) kills tissue cysts immediately (Dubey et al. members of haplogroup 6 can also be found in Europe and Africa (Khan et al... especially heart. 5. 2001a). 1964) characteristics of the infecting parasite may influence the severity of human disease. 2002. Importantly. AIDS patients without antiretroviral treatment may also develop OT but the chance to develop reactivated encephalitis is much higher (Holland. / Progress in Retinal and Eye Research 39 (2014) 77e106 washing of vegetables and fruits (Kapperud et al. goat and horses remained unchanged over time and increase with age of these animals. at least in Europe and North-America which is dominated by three clonal lineages called Type I. gondii of the clonal types I. Especially AIDS patients are at risk to develop reactivated TE. this seems not to be the case. 2006. goats. While Type I T. gondii population in South-America is separated in at least 7 haplogroups (4.01 to 5% depending on the region of the genome analysed (Boyle et al. emergence of atypical strains As already predicted by Hogan (Hogan et al. Based on an estimated neutral mutation rate it was proposed that these three clonal lineages separated and started to expand about 104 years ago (Khan et al. sheep. another important risk factor for reactivation of OT might be pregnancy (Bosch-Driessen et al. At lower temperatures the duration of heating plays an important role. 2011a. a condition which is further aggravated by the fact that those patients are often on potent immunosuppressive drugs. Of note. another haplogroup (i. 1992). Sibley and Boothroyd (1992)]. 3).92 M. gondii is observed in South-America. Classical clonotypes vs. In utero infection is also a considerable risk factor for the development of OT. Villena et al. 2004).. haplogroup 12 or genotypes A/X) is present in wildlife and can also cause human infection (Khan et al. 2012). Seroprevalence is below 5% in slaughter pigs in most industrialised countries (Dubey and Jones.. The risk of human infection by tissue cyst-contaminated meat is dependent on the type of meat. The T. 1989). In most cases. evidence was observed for the occurrence of natural type II-type III crosses under European conditions. 1996). Tissue cysts remain infective in refrigerated meat (1e6 C) and minced meat for up to 3 weeks. The incidence of congenital toxoplasmosis has been evaluated in different countries and is thought to be 3. 2008). Type II or III are only moderately or not virulent. However.. 2009. Seroprevalence of poultry in industrialised poultry farms is very low but higher in free-range poultry. The fact that oocysts are not infective when passed and the short duration of oocyst shedding indicate that direct contact with cats is not a major risk for human infection. gondii infected meat and tissue cysts have been isolated from both meat varieties. 9. and fruits and infrequent hand washing (Jones et al. and pests like mice and rats) (Sibley and Ajioka. 2009). Striking biallelic polymorphisms between these three haplogroups are observed. 2007. suggesting that these lineages arose from just a few crosses between highly similar parental strains (Boyle et al. Wendte et al. isolation or detection of cysts from beef has only rarely been reported (Opsteegh et al. 2011). 2012). However. Among OT patients. gondii has the ability to cross the blood brain barrier (BBB) and form cysts in the brain (Feustel et al.e. There was evidence that most of the immunocompromised toxoplasmosis patients sampled in Europe with non-type II isolates had acquired the infection outside Europe. However. humid regions (p ¼ . Immunology of T. size.0001). A follow-up study revealed that the Th-17 immune response was strong during primary intravitreal infection and markedly reduced upon re-infection of neonatally infected mice (Sauer et al. gondii in the brain and eye. the local immune response in the eye (an immunopriviledged site) is less well studied. However. tumour necrosis factor (TNF).. 2010. Recently. gender. There it growing evidence that the geographic site of sampling largely influences the composition of T. gondii is characterised by the generation of a strong T-helper-1 (Th-1) response orchestrated by CD4þ T cells and dominated by the production of proinflammatory mediators including interleukin-12 (IL-12). host factors might be more important and severe OT may be caused by any parasite type (Holland. 2012. Since immune mechanisms operative in the brain during infection with T. / Progress in Retinal and Eye Research 39 (2014) 77e106 93 for mice the same could also apply for humans. Sousa et al. Dendritic cells (DCs) are likely the key cells that traffic the parasite throughout the body and into the target organs (DCs as ‘Trojan Horse’) (Courret et al.037) (Shobab et al. Peyron et al..2. 2008. there is evidence that sampling biases may have led to an overestimation of the relative importance of T. Maenz et al. Lachenmaier et al. 2012b. In Europe. More recent data from experimental OT models indicate that there is a dysbalance between pro-inflammatory Th-17 and regulatory T-cell responses (mediated by IL-10. Increasing knowledge about the immunopathology of OT may result in new treatment approaches. or recurrence. Interestingly. Serotyping has the advantage that it can be extended also to a healthy population because no parasite isolation is needed (Kong et al. Subauste et al. the prevalence of both serotypes was similar during 3 decades (1981e2009). Boothroyd and Grigg. The NE-II serotype was more common in hot.. i.... However. the following paragraph reviews the key features of the immunopathogenesis of cerebral infection. a novel.. gondii with type I alleles were found associated with postnatally acquired ocular toxoplasmosis in Brazil (Vallochi et al. 2012).. 2013). gondii and differences in mouse virulence are associated with differences in virulence for humans (Ajzenberg. Following dissemination via the blood stream throughout the host during primary infection T. Using an ELISA-based approach it was attempted to associate the serotype in consecutive sera from uveitis patients with OT with age. non-reactive (NR) serotype was significantly more frequently detected in sera of OT patients than non-OT patients (p < . 2013). it is still a matter of debate whether the genotype of T. Strain-specific peptides allow serotyping. . Using an ELISA that distinguishes T. Morisset et al. a technique to determine the clonal type of infection indirectly via the typespecific IgG response.. 2000). 2012. clinical onset. Dubremetz and Lebrun. 2009. 2006. In immune deficient patients. gondii was genotyped from the vitreous humour obtained from patients undergoing vitrectomy (Grigg et al. This observation led to the hypothesis that in immune competent patients the genotype of parasite may dominate the clinical course of OT.. 2001b). 2002. 2001b).. 3. T. NE-II serotype was associated with rural residence (p < . 2004). and nitric oxide (NO). Table 4 Shared and distinct features of infection with T.. 2005b).02) but was also present in other regions. the majority of congenital cases (85%) among pregnant women.001). toxoplasmosis due to immune suppression and OT cases in France (Ajzenberg et al.3. Interestingly. 2002. OT e ocular toxoplasmosis. 3. the strong Th-1 response may also cause immune-mediated tissue damage contributing to the severity of OT. gondii infection The immune response to infection with T. In line with these findings are results from a cohort of 193 patients with congenital toxoplasmosis in North America. Subauste et al. interferon-g (IFN-g). or number of lesions. Interestingly... While the immune response in other organs and the blood has been studied in detail using experimental models of infection.001). Th-17 cells have been identified as key contributors to immunopathological responses in the brain and eye (Furtado et al. Nagineni et al. 2010). whereas immunocompromised patients identified with allele types closely resembling but not identical to the archetypical types I and III (Grigg et al. and Hispanic ethnicity (p < ..01). A similar observation was made in the US when T... 2003). visual acuity. 2010. 2011). 2011). the immunopathogenesis of toxoplasmic retinochoroiditis and toxoplasmic encephalitis is characterized by numerous shared and distinct characteristics (Table 4). By serotyping a dominance of type II specific antibody response in positive but asymptomatic humans sampled in Europe was observed (Maksimov et al. lower socioeconomic status (p < . On the contrary. gondii have been more extensively investigated than those in ocular infection. Th-17 cells are characterised by the production of IL-17 mediated by IL-23 from dendritic cells. regulatory T-cells have been shown to control inflammatory responses thus protecting the host against tissue damage caused by unchecked inflammation. two subgroups of patients could be distinguished based on their immune status. Type II strains account for 70e80% of human infections. TE e toxoplasmic retinochoroiditis.03) and severe disease at birth (p < . gondii type I for humans (Ajzenberg. Feature Passage of biological barriers Cysts formation/latent infection Development of disease in immunocompetent hosts Recurrence in immunocompetent hosts Location of pathology in congenital infection Recurrence in congenitally infected hosts Severe disease in T-cell deficiencies Reactivation triggered by Severe necrosis Standard treatment Brain Blood brain barrier Yes Rarely No Yes No TE Immunosuppression Yes Pyrimethamine sulfadiazine Eye Blood retinal barrier Yes Yes Yes Yes Yes (Severe) OT Unknown Yes Pyrimethamine sulfadiazinea a Dependent on disease severity. gondii serotypes (II and not exclusively II [NE-II]) the NE-II serotype was associated with prematurity (p ¼ . Current understanding is that the strong Th-1 response prevents parasite-mediated host cell lysis by protecting against parasite replication. IL-27. or TGF-b) accounts for the severity of OT. 2006. those with NR serotypes experienced more frequent recurrences (p ¼ . Pathomechanisms and neuro-immunology of T.M.01) (McLeod et al. All individuals affected by strains with type I alleles were immune competent. gondii genotypes observed in humans (Ajzenberg. gondii Both the brain and the eye are considered immune-privileged sites since immune responses in these organs are dampened to protect against damage of vital tissue. location. 2008)... GM-CSF or IL-10 and TNF. antibodies against retinal antigens (Smith et al. 2005). T. and preventing lethal necrotizing TE (Drogemuller et al. and IL-1b inhibited parasite replication (Delair et al.. CCL5 and CXCL8 in retinal endothelial cells. supporting parasite control. 2007). CD4þ T-cells and astrocytes also contribute to resistance and activate CD8þ T-cells by secretion of cytokines (Denkers and Gazzinelli. As brain DCs also show a high level of IL-12 production ex vivo they might be important for maintaining IFNg production by T-cells in the brain. 2011).. Nagineni et al. gondii is remarkably able to control its own fate via modulation of many of the intricate pathways described above that the host uses to try to kill it. 2005a). Scharton-Kersten et al.. Furthermore. During acute TE. There is little doubt that the mechanisms described above allow the host to control parasite replication in the eye. 2012a). Based on their strong expression of costimulatory molecules and the ability to process and present antigen to naive T-cells in vitro brain DCs are important inducers of Tcell responses in TE. i. It was shown in mice with TE that astrocytes are the main producers of the chemotactic cytokines IP-10 and MCP-1 while activated microglia and leukocytes infiltrating across the BBB also secrete chemokines (Strack et al. key components of the immune response in the brain during TE can also be observed in the eye during OT. 1991). Nevertheless. 2003. 2002). CCL11. CD8þ T-cells are essential in resistance due to their cytotoxic action as they lyse Toxoplasmainfected cells during the active phase of infection (Subauste et al. Animal OT models will be categorized .to 100-fold expansion of DCs upon brain infection.1.. As a primary response to infection with T. A proper IFN-g production in turn is inevitable for successful host resistance against infection with the parasite. Similarly. While DCs cannot be detected in the brain parenchyma of healthy hosts. TNF-a. gondii-infected brains on one hand favours parasite survival therefore aiding chronicity of the infection but on the other hand is well known to dampen overwhelming (detrimental) inflammatory immune responses (Wilson et al. CD4þ and CD8þ T-cells migrate into the CNS and activate resident microglia cells (Gazzinelli et al... gondii interferes with multiple arms of the innate immune system to ensure an environment suitable for sustained parasite growth in the absence of severe pathology. and for levels of CCL2. and vitreous fluid in chronically infected animals. 1996).. Similar observations were made for levels of chemokines including CCL2. The marked increase might be explained by the development of DCs from infiltrating blood monocytes.. 1994a). the most important inducer of IFN-g synthesis (Gazzinelli et al. 2007. In this regard.. bradyzoites released from cysts convert into tachyzoites resulting in lethal encephalitis if left untreated (Dellacasa-Lindberg et al. the recruitment of meningeal DCs. Experimental approaches to study ocular toxoplasmosis 4. the presence of autoimmune reactivity against retinal antigens has been described as a protective factor against severe OT (Vallochi et al. IL-12.. 1994b). the proliferation and differentiation of perivascular macrophages or the development of brain DCs from intracerebral progenitors or resident microglia. gondii macrophages.. Maenz et al. Suzuki.. 2003).. / Progress in Retinal and Eye Research 39 (2014) 77e106 Lachenmaier et al. astrocytes possess a crucial role in maintaining immune-regulatory functions during CNS infections with T.. 2009).. 2011). the strong immune response most likely contributes to the pathology that develops in the eye. while IL-10 and IL-6-deficient mice showed increased inflammatory responses and necrosis (Lu et al.. 1990. Immunosuppression of the host as in the case of AIDS and transplantation may lead to the uncontrolled release of parasites during rupture of tissue cysts in the brain of latently infected individuals. Montoya and Liesenfeld. The recruitment of DCs to the CNS seems to be dependent on the signalling through multiple chemokine receptors and possible changes in the affinity of the leukocyte integrin LFA-1 (John et al.. 1997). However. Mice lacking nitric oxide (NO) production develop severe necrotizing lesions and uncontrolled tachyzoite replication in the CNS during chronic infection (Khan et al.. Subsequently. In summary. Our knowledge regarding the local immune response in the eye during OT is less detailed than that of the immune response in the brain. IL-6. an essential amino acid for T. In the 1950s researchers spearheaded this endeavour by presenting a mouse and guinea pig model (Hogan. gondii-infected HIV-positive patients not receiving antiretroviral therapy may develop toxoplasmic encephalitis (TE) (Grant et al. CXCL8.... It is well documented that a CD4þ T-cell count of <200/ml renders a seropositive patient susceptible to reactivation and the onset of TE (Nascimento et al. Chemokine secretion is in turn responsible for an enhanced neuroinvasion of leukocytes as astrocyte derived MCP-1 can mediate the migration of monocytes across an in vitro-model of the BBB. brains of chronically infected mice show a 50. 2009). Experiments with TNF. 1980) and in unaffected humans (Furtado et al.. The production of IL-10 in T. 1989. 4. Animal models For a long time experimental researchers have strived to establish animal models for OT. monocytes. the inflamed brain appears to induce specialized structures that guide the migration of T-cells in this immune-privileged environment whereas pre-existing scaffolds for guidance of lymphocyte migration exist in other tissues... Munoz et al.. 1992. and as many as one third of all T.94 M. Astrocytes and microglial cells become activated by IFN-g and are major effector cells in the control of parasite replication via secretion of IL-1. 2002). In seropositive AIDS patients cerebral toxoplasmosis is among the most frequent CNS pathologies. In mice which lack the signaltransducing receptor gp130.. appears to be involved in the protection against parasite replication (Delair et al. a number of researchers have proposed an autoimmune component in the eye that contributes to pathological changes during OT (Zamora et al. 1958) and since then remarkable progress has been made. 1991. More recently.. 2004) as well as T-cells that proliferate in vitro when encountering retinal antigens have been described in patients with OT (Nussenblatt et al. L-tryptophan. granulocytes and dendritic cells secret pro-inflammatory cytokines. CXCL9 and CXCL10 in sera of patients with toxoplasmic retinochoroiditis (Goncalves et al. Activated antigen-presenting cells together with IFN-g support the proliferation of CD4þ and CD8þ T-cells that are subsequently recruited to the brain. In addition. Thus. Mamidi et al. Schlüter et al. Hogan et al. Treatment with inhibitors of nitric oxide production has resulted in increased inflammation in the choroid. 2011). respectively. and TNF/lymphotoxin-a-deficient mice revealed that TNF receptor type I-mediated immune reactions influence NO production and are crucial for the survival of mice with TE (Schlüter et al. gondii. The movement of infiltrating cells was associated with an infection-induced reticular system of fibres (Wilson et al. Wyler et al. T. stimulation of retinal endothelial cells with IFNg. 2001). gondii by containing inflammatory lesions. 2002). 2004). retina.. 2008). 1951. During TE a microglial upregulation of adhesion molecules like LFA-1 and Mac-1 appears to drive the infiltration of leukocytes into the brain. 2009). 1997. or IL-1b resulted in increased ocular lesions associated with increased tachyzoite dissemination (Gazzinelli et al. TNF-a. 1998.e. lymphotoxin-a-. Experimentally infected mice developed focal ocular inflammation of the pigmented epithelia of the retina and suppression of IFN-g.... 2008). 1992. 1968)... Typically.. 2005. Strategies to provoke OT recurrences by systemic immunosuppression (Cyclosporine A or total lymphoid irradiation) failed to induce relapsing retinochoroiditis. 1986. gondii on the manifestation and progression of . Newman et al. Subauste.. d) disease diagnostics e) parasite strains utilized. 1968). spiramycin. 2011. irido-cyclitis as well as retinal detachment and necrosis (Table 5). 2011. 1984.. Holland et al.. gondii tissue cysts by IHC is time consuming and cumbersome. 1982).. administration in outbred hamsters (Culbertson et al. 1988b. / Progress in Retinal and Eye Research 39 (2014) 77e106 95 along the following criteria: a) parasite entry. However. Nozik and O’Connor. failed to yield any results (Nozik and O’Connor.M. Me49. 2003).5. Self-limitation of disease and recurrence Induced toxoplasmosis in laboratory animals was typically selflimiting when strains avirulent for mice (type II) were utilised. 1996).p. RH. Pronounced vasculitis was noted when fluorescence angiography was used to detect clinical disease manifestations in mouse and feline models of OT (Davidson et al.. 4. Due to the scarcity of retinal cyst formation in this particular model a reduced cyst count could not be determined (Gormley et al. A rabbit model for injury induced relapse.e. gondii have recently been published (Munoz et al. in particular the limitations of previously used animal models will be highlighted.. b) onset of disease and manifestation.. c) self-limitation of ocular inflammation and models of recurrence. Where funduscopic examinations were conducted white diffuse retinal lesions could be observed in various test species. 1988b). None of the tested antibiotics change the clinical course (size of lesions and disease progression) of OT in test animals. When mouse-virulent Toxoplasma strains (type I) were tested or inbred gene-modified mouse strains with immune-deficiencies (IFN-g k. Additionally.. intraperitoneal administration of infectious T. 4. however. However. even after secondary challenge with T. retinochoroiditis. 9) (Holland et al. 1998). A more rapid methodology consists of tagging the parasite with a b-Gal expression cassette as demonstrated by Escoffier and colleagues (Escoffier et al..3. vitreous. 9) (Dukaczewska. Davidson et al. In a cat model and nonhuman primate models of OT intra-carotic injection of tachyzoites was attempted and good parasite dissemination and ocular inflammation was achieved (Davidson et al. Signs of inflammation usually include vitritis. Gormley et al. To study congenital toxoplasmosis i. 2003).. intra-retinal or supra-choroidal injection sites result in reproducible. 1993. 4. Overall the degree of ocular inflammation in laboratory animals frequently exceeds what is seen in humans. Onset of disease and manifestation Depending on methods of infection disease onset was noted as shortly as two day post intra-ocular inoculation in non-human primates and up to 3e6 weeks after i. was the observation that clindamycin was not well tolerated by hamsters resulting in a 100% mortality which could only be prevented by simultaneous administration of vancomycin. Introduction of T. PLK. neutralising INF-g reliably caused recrudescent systemic toxoplasmosis and OT (Olle et al. gondii (Friedrich et al. Immunohistochemic analysis of ocular tissues usually revealed profound changes in the retinal architecture with crypt formation. On the other hand. Gormley et al. Depending on animal species tested ocular inflammation resolves after 3e8 weeks. Gazzinelli et al. yet often in swift and severe inflammation. injections of pregnant mice resulted in intra-uterine transmission of the parasite and disease manifestation. 1986). Likewise. 1998.2.1994a. Test animals succumbed rapidly to generalised toxoplasmosis and showed no signs of ameliorated OT symptoms (Davidson et al. 2003). Immunomodulation & immunosuppression Several investigators studied the effects of altered immune responses to T. McMenamin et al. Norose et al.. Nozik and O’Connor. depending on parasite strain and size of inoculum.4. The points above shall be discussed in more detail hereafter. Norose et al. f) experimental manipulation of disease progressing and treatment. gondii.6. Norose et al. and Fukaya) of T. Only few studies performed per-oral administration of tissue cysts with promising results with regard to disease penetration and manifestation (Johnson. 1999. Contrary to the findings reported above.. isolated from patients or animals. Beverly.1. 2003). Furthermore. In several species ocular inflammation ensued frequently in conjunction with systemic disease or TE.. clindamycin. being most excessive in models of intra-ocular injection of Toxoplasma tachyzoites. A noteworthy result of this study. migration of ganglial as well as RPE cells (Fig. 4.1. 1984.1.. atovaquone significantly reduced the number of brain cysts measured at a late chronic stage of disease. This infection method is however difficult to reproduce in smaller animal species and thus will remain unusual.) were studied. By today’s standards intra-ocular injections are considered too artificial either due to the fact that parasite entry does not mimic the physiological route or due to concerns of additional ocular damage stemming from physical trauma to ocular tissues or the breach of the anatomical and immunological barrier following injection. The most physiologic method of infection to study acquired OT is the enteral route. Maenz et al. gondii tachyzoites or tissue cysts is the most frequent route of infection in the study of toxoplasmosis.. both systemic and ocular was noted (Dutton et al.. Two recent reviews that focus on murine models of infection with T. 9F) (Culbertson et al. attempting to rupture toxoplasma cysts mechanically.. 1970). 1998).1. Hay et al. 1993. 2012).1. In several instances. 2011.. application of clindamycin in a cat model of OT showed paradoxical adverse effects.1993. the inflammation may spread systemically and result in the death of the test animals.o. Norose et al.1982. 4. Several studies established the presence of toxoplasmic cysts in retinal tissues across several species (Fig. Experimental manipulation of disease course To elucidate OT pathomechanisms and treatment options various attempts to alter the disease progression in animals have been investigated. gondii into the anterior chamber. 2010). 1996). in rabbit and monkey models of OT pigmented scars were observed after disease remission (Fig. Type II strains of T. death of test animals was a frequent result (Hu et al. intra-ocular infections resulted in more rapid disease onset. no atypical or non-canonical strains have yet been tested in animal models of OT as well as true clinical isolates from patients with OT although at least one such strain exists (Chai et al. granulomatous immune cell infiltrates and retinal oedemas were observed. administered clinical doses of conventional antibiotics (pyrimethamine/sulfadiazine.. 2012).1.... To achieve a more localised immune response intraocular injections have been performed.. A physiological spontaneous model for recurrence has not been established yet. 1982. For better reference hallmark studies and important animal models are summarized in Table 5. Detection of T. Pathogen strains Most studies used common laboratory strains (i. However. not in all studies the observation time span was long enough to establish that fact with certainty. in a rabbit model of acquired OT Tabbara et al. (1974) reported a positive effect of clindamycin demonstrated by accelerated remission and a markedly reduced damage to the retinal architecture.1. Parasite entry/methods of infection In general. gondii and to a lesser extent type I strains are used in animal models of ocular infection. atovaquone) used in the treatment of OT.p. 4. In a hamster model of OT Gromley et al. 50. remission @ brain disease 12 weeks suspension FS. 1982) Abbreviations: AC e anterior chamber. FA e fluorescence angiography. no systemic 6 weeks PI.o.. clindamycin drug study 1968. ME49 C57Bl\6 Me49 5 cysts II AC 5000 tachyzoites INFeKO mice died after 11e12 days.. 10000 tachyzoites for 4 (104 tach. No IHC (Norose et al. 1970. breach lesions peak @ 3 weeks. 500 tachyzoites First signs 5e8 days. iritis. role of INF-g. Species Species strain T. artery IgM of BRB. / Progress in Retinal and Eye Research 39 (2014) 77e106 Role of FAS-FAS-L I. 1974) Model development (Davidson et al. retinochoroiditis. 2005. Retinochoroiditis. peak @ i. cyclitis after 20 days. 1995) (Gormley et al. Charles et al. Retinochoroiditis after 2e3 weeks. vitritis. FA. vasculitis. 2011) II Hamster Hamster Outbred Syrian golden outbred California pigmented þ others Outbred Me49 Me49 II II Rabbit Beverley II Cat Me49 II Outbred Nonhuman primates RH I yes FS. choroidal tachyzoites 2e3 weeks.p. (Pavesio et al. 10. INFeKO PLK WT C57/BL6. No Brain > posterior retina > peripheral retina > choroid > BAG1. IHC.. focal (macula) tachyzoites granuloma @ 10 days. Fas-L-k. IHC. FAS-ko (B6-lpr).2 ml mouse (few) at posterior pole. scars after 2 month. FA optic nerve All ocular tissues Clinical score.. RH SAG1 k. Yes Tapetal fundus destruction. IHC Yes Retinal scars þ necrosis..p. multiphoton microscopy i. . Norose et al. i. p. Brain. 2007. (Nozik and O’Connor. Similar models are grouped together in one row. resolution hypopyon..o. WT mice survived over a month Ocular inflammation day 6e7 in WT. WTBalb/c.o. Dose Course of infection Organs tissues involved Diagnostics Retina Study purpose cysts present Role of INF-g Reference Mouse Mouse Mouse Mouse Fukaya WT C57/BL6. 20 cysts Peak of chorio-retinitis @ day 35 Predominantly retinal damage. Tabbara et al. 1993) Model development (Culbertson et al. protective (Charles et al. Me49 less severe or 6 days damage p.. IHC.o. 1999) M. VH e vitreous haze. Maenz et al.96 Table 5 Compilation of essential animal models of OT. systemic disease in k. FS. 25. ERG. FS e funduscopy.. VH 3e5 weeks Visually. No 100 cysts lesions FS. ocular Carotid serum antibodies retinal degeneration. gondii Geno. PD-L1. IHC e immuno-histochemistry. 2010) MHC-2 Role of CXCL10 and T-cell recruitment Model development Drug therapy trial on active and chronic OT (Norose et al. PI e post infection.o.p 0. resolution aqueous flare. II Retinal damage after 6 days Intra-vitreal 1000. e per-oral. e intraperitoneal.o. 1998) Model development. moribund QC-PCR for SAG1. 2003) (Hu et al. resolution 21e70 days injection vasculitis. (B6-gld) WT C57/BL6 RH. IHC Yes White retinal lesions starting FS Beginning @ 10e14 PI. low fever 2e3 days PI Intra-retinal 5Â103e1Â106 Retinochoroiditis.).. peak retinal detachment (trauma). optic nerve No Role of SAG1. PCR necrosis.Route of strain type infection II p... IHC Yes Retinitis 1e2 days PI. Supra1000e2000 7-10 days PI lesions. vitritis. retina Serum antibodies. E À RPE migration into various retinal layers 41 days post per oral infection.. mice following intra-vitreal injection of T.. 1982. those results could not be fully reproduced when i. d) size. a lack of inducible T-cell apoptosis (an important part of the ocular immune privilege) may result in more excessive tissue damage. and IL-10 were all necessary to vaccine-induced resistance to ocular challenge. The ambivalent role of T-cell responses in OT was highlighted in a mouse model of intra-cameral tachyzoite injection of PLK tachyzoites (Hu et al.. B-cells.1.. which allows uniform assessment of disease progression. distribution and localisation of retinal lesions ought to resemble the human situation. 2003. c) predominant retinal involvement.. In a seminal study in mice Gazzinelli et al. A good benchmark is the model of experimental autoimmune uveitis. Administration of neutralising antibodies to both Th-1 cytokines led to an aggravated course of ocular disease and increased dissemination of tachyzoites. Lu et al. symptoms not seen in immune competent animals. IL-17A... g) pharmacological interventions in humans should also be applicable in the animal model. From our current understanding an animal model for ocular toxoplasmosis should fulfil the following requirements: a) parasite entry similar to the human situation b) self-limiting disease and possibility for recurrence.e. Culbertson et al.. CD4þ and CD8þ T-cells. Various animal species e such as rabbit. However. 2004) showed that cells and molecules characteristic of Th-1 immune responses contribute to control of parasite replication in the eye but also mediate inflammatory responses. Some of the requirement formulated above may never be met due to anatomical.o. 1995). Caspi et al. 2003. CXCR3) was reduced (Kikumura et al.. 2001). mice (Norose et al.o... mice and calomys have been investigated (Charles et al. 2008). left fundus e active OT lesion 1 week post inoculation.. a consensus scoring method for OT associated ocular inflammation should be developed. C e Non-human primate: funduscopic montage from eyes injected intra-ocularly with T. gondii (Pavesio et al. where mouse strains. Apart from more severe ocular inflammation including dry vasculitis an increased parasitic load was observed in ocular tissues particularly the choroid and the optic nerve. 2012). disease induction and scoring methods have been firmly established (Caspi. progression and resolution have corresponding human counterparts. Maenz et al. B e Rabbit: diffuse retinochoroidal scars after 42 days post intravitreal injection into a naïve animal. 1999). 2012). Norose et al. In recent years a clear trend towards mouse models can be observed. For practical reasons a mouse model is most desirable and it remains to be established which genetic background is most suitable for OT induction. gondii.. The ocular lesions were characterised by severe retinochoroiditis including retinal necrosis. 2003. non-human primates. 1970. an OT animal model should mimic the human condition as closely as possible.. RPE atrophy and/or hypertrophy. gondii inoculated intracamerally ocular pathology and ocular protective immunity was induced (Lu et al. 1998). hamster. D e IHC of per-orally infected C57BL/6 mouse: strong disturbance of the retinal architecture with cone formation (protuberance of the photoreceptor layer) and lymphocyte infiltrates 21 days post infection. Davidson et al. 2005. 1968.p.. Tabbara et al. biochemical and immunological differences . In a series of experiments using the intracameral route of infection. A certain degree of standardisation is required to make data more comparable and to allow for multi-centre studies to accelerate the research of OT. 1993. CCR5. Lack of both T-cell subpopulations led to vastly higher numbers of cysts in retina and brain as well as increased ocular inflammation. h) the ability to differentiate between congenital and acquired toxoplasmosis. (2010) revealed loss of PD-L1 and MHC-II expression in IFN-g -k. 9. gondii tissue cyst in the inner plexiform layer detected 21 days post per oral infection. / Progress in Retinal and Eye Research 39 (2014) 77e106 97 Fig. 4. 1999. Conclusions Naturally. A further analysis of IFN-g functions by Charles et al. hyperplasia and an almost complete destruction of the retinal architecture. Nozik and O’Connor. arrow marks the injection site (Garweg et al. F e T. f) parasite strains prevalent in humans should be investigated. 2003). The effect of neutralizing the cytokines IFN-g and TNF-a was even more striking in this study. e) immunemechanisms which lead to disease manifestation. (2005. 1995. 2009).M. 2007.. 1988b). Pavesio et al.functionality on ocular tissues or lymphocytes resulted in an exacerbated disease. experimental OT. Images D-F courtesy of Agatha Dukaczewska (Dukaczewska. This observation indicates that although T-cell function is crucial in controlling intra-ocular infection. injection of tissue cysts from strain Me49 was used (Shen et al. Funduscopic and IHC images of various OT animal models: A e Hamster: focal retinal inflammation 2 weeks post intraperitoneal injection of T. cat.7. right fundus e retinochoroidal scar surrounding the injection site 4 month post injection (arrow) (Holland et al. Furthermore. (1994a) found that both CD4 and CD8 cells were crucial to curb ocular inflammation after intraocular infection with the avirulent strain Me49. An upregulation of Fas-FasL was noted as a result of ocular inflammation and lack of either Fas or FasL. gondii type I tachyzoites and chemokine mRNA levels of various chemokines and cytokines (i. Norose and colleagues confirmed the protective role of IFN-g in a similar mouse model utilising a per-oral feeding method of tissue cysts to infect IFN-g -k. 1974). CCL3-5. Hu et al. Using an avirulent strain of T. Prevention Improvement and worldwide implementation of primary and secondary prevention and prophylactic strategies to reduce human infection are strongly indicated.. 2008. hospitals. cell line ARPE-19) it could be determined that secretion of proinflammatory cytokines such as IL-1b.e. health care authorities and medical personnel.. Despite considerable efforts no human vaccine is on the horizon. Scorza et al. 2013). gondii has not been answered satisfactorily. Nevertheless. Nagineni et al. which need to be addressed in future research: 5. The relevance of other presumed factors (route of infection. If confirmed. . Mevelec et al. A Development of a human Toxoplasma vaccine preventing OT. In a chick embryonic model of retinal infection it was determined that T. Future directions Although our knowledge on the pathogenesis. by increased meat consumption in developing countries.2. age of patient) that may contribute to reactivation and recurrence of disease need to be clarified. gondii-free water for all households.. A T.ToxovaxÒ. 5. a membrane protein which has also been shown to facilitate tachyzoite migration across retinal endothelium (Furtado et al.. but subsequently failed to achieve wide-spread use. Future developments may focus on DNA based immunisation strategies.2.. The following list summarises unresolved topics. Additionally. 4. gondii harms its host organism. the opposite may be true in regions with strong population growth and urbanisation trends i. This obstacle applies to almost all animals models for human conditions and should not discourage researchers from ever improving OT models. This may also be associated with spread of more virulent parasite strains. Jongert et al. domestic cats vaccinated against T.. Several vaccines developed for veterinary use in cats and ovines have shown efficacy in initial stages. and potent immunomodulatory molecules (i. 1996). A T.e. Primary prevention needs to address: A better communication of hygiene measures through schools. 1996). 1991. 2008). In regions undergoing rapid industrialization. A maternal screening and treatment to prevent congenital (ocular) toxoplasmosis. murine models of OT will continue to provide valuable information on key topics of interest. A All these measures need to be assessed on their impact on disease prevalence... this observation could be an important mile stone in our understanding of the immunopathogenesis of OT. gondii infection.e... 2003. A Already in the near future a detrimental effect on OT numbers can be expected facilitated e. 4. and moreover tachyzoites were able to transmigrate RVE monolayers in an ICAM-1 dependent manner (Furtado et al. many questions are still open. gondii and by which means the parasite traffics through the eye.98 M.2. ANXA-1) is a common feature after infection (Mimura et al. congenital infection and parasite persistence. Host cell response to parasite entry In a series of experiments utilising human retinal pigment epithelial cells (HRPE. Buxton and Innes. 2000. Maenz et al. 1995). i. we still lack a complete picture of its global prevalence and the rate of new infections. / Progress in Retinal and Eye Research 39 (2014) 77e106 between host animals and humans. gondii infected leucocytes are the preferred method of parasite spread throughout the body. 2009). suffer from cumbersome production processes and limited shelf-lives and additionally are potentially hazardous for the administrating person.e.1. since RVE cells unsurprisingly also allowed transmigration of infected DCs efficiently (Furtado et al. GM-CSF. 2012b).2. In vitro experimental models Compared to clinical data and animal models for OT in vitro studies are relatively scarce and focussed on factors that influence parasite growth and infection capabilities or response of host cell types to T. T-263) (Frenkel et al. which utilised live mutant parasite strains (i.. 2003.. However. gondii prevalence in humans may also increase in many regions of the world as a result of changing environmental conditions as predicted by global climate variability (Meerburg and Kijlstra. The question which ocular cell type is predominantly infected by T. Epidemiology A Although OT causes a high health burden.. 2012. large parts of Asia (Zhou et al. clinic and treatment of OT has substantially increased over the last years. gondii and treatment with antiparasitic drugs. gondii infection by upregulation cellular adhesion molecules ICAM-1 (Nagineni et al. TGF-b1. 2009). 2004. in the case of feline vaccines.. where the antigenic protein/peptide is synthesised in-vivo by the immunized host. 2005. 2012b)..g. A The proper assessment of disease burden and in particular the assessment of Quality of Life measures in patients will be helpful for raising awareness and grant public support for future research and prophylactic measures. basic mechanisms of ocular infection with T. 2009.1. in a recent promising study using human explanted eye cups [donated cadaverous eyes] it was observed that tachyzoites preferentially infect glial cells rather than cells of neuronal ontology (Furtado et al. gondii (Smith et al. 2004).. Whereas in western industrialised countries a decreasing T. 4. Furthermore. Parasite replication and infectious capabilities Tachyzoite replication and subsequent spread throughout tissues is the dominant disease mechanism by which T... In HRPE cells parasite growth could be reduced by adding IFN-g and TNF-a (Delair et al. Zamora et al. Nagineni et al.. such as China. gondii seroprevalence was observed. gondii may still shed infectious material thus failing to prevent livestock or human infections via the faecal route (Innes et al.2. 2000). TGF-b1. HRPE cells respond to T. A set of experiment conducted by Smith JR and colleagues investigated the role of the retinal vascular endothelium (RVE). RVE cells could be readily infected with T. Fachado et al. the demand for meat has already increased enormously. 2003).. Mohamed et al. 5. 2011).. gondii proliferation could be attenuated by inhibiting host enzymes (ornithin decarboxylase and arginine decarboxylase) essential for the polyamine synthesis in the protozoan parasite (Moraes et al. Veterinary vaccines. A Secondary prevention on recurrence prophylaxis needs to identify individuals at risk as well as the impact of parasite strain virulence. 2002). Vaccination attempts in partially humanised mice and various other species have shown promising results to some degree (Couper et al. Furthermore an important question with regard to OT manifestation and pathophysiology in humans is the question which ocular tissues are preferentially infected by T. 2012a). IL-6. This observation does not necessarily contradict the current popular “Trojan horse” hypothesis which states that T.. S48. 2003. The mechanism is believed to be NO-independent yet IDO dependent (Nagineni et al. we would like to thank Agatha Dukaczewska and Prof.. Lehoang.. The following miles stones need to be achieved: A Better integration of in silico. Filisetti. Aspinall. L. 2003. Balansard. 25e27. Islam.E. Bahia-Oliveira. 2006. Aubert. Funding The authors Maenz. 2005. P.L. Necrotising retinopathies simulating acute retinal necrosis syndrome. Pujol... Schares. Treatment AGiven the risk of a potential life threatening and blinding condition. Sautter... Bonnabau. C.. W. H.. A. Pratlong. Jager. 24. Asatova. A. Since imaging technologies are fast advancing with constantly higher resolution. Flori. Bessieres. M.C. Hyde. Menotti...E. F. Ignazio Tedesco for providing IHC eye sections and images of mice affected by OT.1. Ajzenberg. Frank Seeber (RKI.E. Brazil. 2009.. Microbiol. Chimeric antigens of Toxoplasma gondii: toward standardization of toxoplasmosis serodiagnosis using recombinant products. The establishment of improved animal models for OT mimicking human infection is potentially helpful. J. 33 (1). and Pleyer received funding from the Federal ministry of education and research of Germany (BMBF) through the Toxonet 02 research collaboration.. Cuisenier. Mosk. Mahdavifard. A major problem of OT is recrudescence of the disease due to reactivation of persisting parasites.. C. Detection of Toxoplasma gondii in aqueous humour by the polymerase chain reaction. M. Maenz et al.. 2002. Franck. A.4. Ashrafunnessa. small incremental steps such as the exploration of intravitreal drug administrations (i.. Larger prospective studies are required to address clinical aspects of OT. N. Sims. M. Roberts. Highly endemic... Currently. Spadoni. B.. S.N. may prove indispensable for better disease evaluation and the decision making process with regard to therapeutic and preventative measures.F. Bodaghi. J. prognosis and pathogenesis of OT [see also Section 2.A. Molecular evidence for multiple Toxoplasma gondii infections in individual patients in England and Wales: public health implications. P.D... Spectral optical coherence tomography has been applied to assess the morphological changes associated with OT and already allowed in vivo follow up on morphological changes. Khatun.. Fardeau.M.G. Pathangay. Amendoeira.. Seroprevalence of toxoplasma antibodies among the antenatal population in Bangladesh. However. P. Kauffmann-Lacroix. C. R. Orefice.. C. M.. D. Oswaldo Cruz 104. Beghetto.L.. Berlin) and Astrid Tenter (TiHo Hannover. gondii accesses the retina is not yet clear.. L. Alves. Ophthalmol. The IFNgamma þ874T/A gene polymorphism is associated with retinochoroiditis toxoplasmosis susceptibility. Another promising option such as Raman technology may also allow non-invasively analysis of intraocular fluids by in vivo antibody analysis (Elshout et al.C.. Jones........ P. Direct in vivo identification of infectious organisms became available for parasitic and fungal keratitis using confocal microscopy and open new perspectives.. J...R. K..H.. Obstet. 2133e2140. M. L.1.. Gargano. A Standardisation of OT models: The most suitable genetic background of laboratory test animals remains to be determined. Noble.T. B.. 5... Rozenberg. J. 451e455. Villena. Rabiah.. Gross.H. Pleyer. H. Dis. Ophthalmol. Parasitol.A. 77. A Prospective clinical multicentre trials addressing course. T.2].I.. 1155e1167. F. and correlation with clinical findings. F. Mets. Infect...... 97e103. Paris.V. in vitro and in vivo experiments: Promising drug targets can be obtained from in silico prediction and interesting results have been obtained from in vitro experiments.. I.. P. Infect. D. gondii’s genetic structure will be highly beneficial in this endeavour [see Section 3.. The current animal models of OT only partially reproduce the human disease. L. gondii cysts from eye and brain is an important treatment goal. Genotype of 88 Toxoplasma gondii isolates associated with toxoplasmosis in immunocompromised patients and correlation with clinical findings. animal models are of crucial importance to progress our understanding of the pathogenesis of OT. peptide microarrays and our ever growing understanding of T.. Rabodonirina. Leandro.... H. Joynson... F. J. M. Huq. Carme. S. Gynaecol. Darde. Latkany. 199. H.. 89.. Paris.. W. 39e46. Pathophysiology The mechanisms by which T.. 841e843. A..F. 2011). 2003.C. F. diagnostics. 2009. D. 107e109. Swisher. Filisetti. K. 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