Ocular toxoplasmosis (OT) is a persistent vision-threatening eye infection caused by the parasite Toxoplasma gondii (T. gondii), and the main cause of posterior uveitis in the world. Despite current treatments, parasites are not eliminated from the eye and can cause OT recurrences, the main clinical problem associated to OT. The exact mechanisms involved in this reactivation remain unknown. Population studies suggested that single nucleotide polymorphisms (SNPs) in the locus of interleukin-1 alpha (IL-1α) gene (IL1A) are involved in OT recurrences. In murine models of toxoplasmosis, IL-1α produced by resident microglia was suggested to control parasite burden and the immune response in the brain. In the eyes, retinal microglia and their contribution to OT have been poorly explored. Therefore, this study wants to investigate the role of retinal microglia in the pathophysiology of OT. We hypothesize that retinal microglia is the direct link between OT reactivation and IL1A-SNPs, causing altered IL-1α function, and predisposing patients to OT recurrences. To tackle this, we propose a bed-to-bench translational approach, involving genotyping of OT patients, specific genetic ablation of IL-1α from retinal microglia in an OT murine model, and in vitro modeling of IL1A-SNPs within human-induced pluripotent stem cell-derived microglia (hiPSC-microglia). We expect to provide a risk assessment tool for reactivated OT patients and unveil molecular mechanisms of retinal microglia and IL-1α cytokine with high therapeutic potential against OT reactivation.
DFG Programme
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