Latent Cerebral Toxoplasma Gondii Infection Induces the Kynurenine Pathway and Production of Neurotoxic Metabolites.

Abstract

The kynurenine pathway (KP) has been implicated in a broad range of neurological disorders. KP activation in brain resident immune cells, including astrocytes and microglia, contributes to the release of neuroactive metabolites with strong impact on neuronal functions. KP activation is triggered by inflammatory cues, however the contribution of chronic brain infections on KP activation remains poorly explored. Toxoplasmosis is 1 of the most common infections caused by protozoan parasites. Infection of immuno-competent individuals is characterized by bradyzoite-containing cyst development in neurons, leading to life-long chronic infections. Control of latent toxoplasmosis relies on an IL-12-induced T-cell derived IFNγ response, and results in a sustained inflammation of the brain characterized by activation of recruited and resident immune cells. Here, we investigated a possible link between induction of a persistent neuroinflammation induced by Toxoplasma gondii long-term infection, modulation of the KP and production of key neuroactive metabolites. Our findings demonstrate that chronic infection with either of 2 Toxoplasma gondii strains- causing encephalitis and the other inducing latency-leads to sustained activation of the KP, resulting in increased production of quinolinic acid, an excitotoxic metabolite known to have detrimental effects on neurons.