Pathophysiology of ocular toxoplasmosis: Facts and open questions

Abstract

Infections with the protozoan parasite Toxoplasma gondii are frequent, but one of its main consequences, ocular toxoplasmosis (OT), remains poorly understood. While its clinical description has recently attracted more attention and publications, the underlying pathophysiological mechanisms are only sparsely elucidated, which is partly due to the inherent difficulties to establish relevant animal models. Furthermore, the particularities of the ocular environment explain why the abundant knowledge on systemic toxoplasmosis cannot be just transferred to the ocular situation. However, studies undertaken in mouse models have revealed a central role of interferon gamma (IFNγ) and, more surprisingly, interleukin 17 (IL17), in ocular pathology and parasite control. These studies also show the importance of the genetic background of the infective Toxoplasma strain. Indeed, infections due to exotic strains show a completely different pathophysiology, which translates in a different clinical outcome. These elements should lead to more individualized therapy. Furthermore, the recent advance in understanding the immune response during OT paved the way to new research leads, involving immune pathways poorly studied in this particular setting, such as type I and type III interferons. In any case, deeper knowledge of the mechanisms of this pathology is needed to establish new, more targeted treatment schemes.

Fig 1. The eye and the BRBs.

(A) The internal BRB isolates ocular tissues from the blood stream via tightly sealed endothelial cells, surrounded by pericytes, and Müller cell and astrocyte extensions. (B) The retina displays a stratified organization reflecting the localization of the different cell types fulfilling specific roles. The choroidal vascular system is separated from photoreceptor cells by tightly connected RPE cells, which adhere with their vascular pole to the basal Bruch membrane, forming the external BRB. BRB, blood-retinal barrier; RPE, retinal pigmented epithelial.

Fig 2. The ocular immunosuppressive microenvironment widely impairs the normal immune response to T. gondii infection.

In the general situation, the lysis of the parasitophorous vacuole and, ultimately, the parasite, relies on the expression of IFNγ by multiple cell types stimulated with various T_h1 cytokines. In the eye, this mechanism is impaired by the presence of inhibitory molecules locally expressed by retinal cells, including RPE cells. Green arrows with pointy heads mean “activates/stimulates.” Red arrows with flat heads mean “inhibits.” αMSH, α-melanocyte-stimulating hormone; CRE, cAMP response element; GBP, interferon-induced guanylate-binding protein; IDO, indoleamine 2,3-dioxygenase; IL, interleukin; IFNγ, interferon γ; iNOS, nitric oxide synthases; IRF1, interferon regulatory factor 1; IRG, immunity-related guanosine triphosphatases; LT4, CD4+ T cells; LT8, CD8+ T cells; MΦ, macrophage; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-kappa B; NKC, natural killer cells; PNL, polymorphonuclear leukocyte; TGFβ: transforming growth factor β; TNFα, tumor necrosis factor α; Treg, regulatory T cells.

Fig 3. Proposed model of the immune response to the retinal infection with Toxoplasma gondii.

Evidence suggests that the infection of retinal cells with T. gondii results in the expression of IL17 by resident cells (Müller cells, but maybe also T_h17 T cells), which might be responsible for the recruitment into the retina of activated immune cells, facilitated by the increased permeability of the external blood-retinal barrier. These immune cells would be responsible for subsequent retinal lesions, probably also by suppression of Treg cells (not shown). At the same time, IL17 expression negatively interferes with IFNγ production, thereby diminishing the protective antiparasitic response. IFNγ, interferon gamma; IL17, interleukin 17; Treg, regulatory T cells.