Latent Toxoplasma gondii infection increases soluble mutant huntingtin and promotes neurodegeneration in the YAC128 mouse model of Huntington’s disease
AbstractToxoplasma gondii causes a prevalent neuroinvasive protozoal pathogen that in immune competent individuals results in latent infection characterized by intra-cellular parasite cysts in brain. Despite life-long infection, the role of latent toxoplasmosis on chronic neurodegenerative processes is poorly understood. Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a dominant CAG repeat expansion in the huntingtin gene (HTT) that results in the expression and accumulation of mutant huntingtin protein (mHTT). The mutant HD gene is fully penetrant. However, there is significant variability in disease progression that is in part explained by as yet unidentified environmental factors. The kynurenine pathway of tryptophan metabolism (KP) is an inflammatory pathway and its activation is implicated in HD pathogenesis. KP upregulation also occurs in response to infection with Toxoplasma gondii suggesting that the latent infection may promote HD. We discovered that mice on the FVB/NJ background develop latent toxoplasmosis following infection with the ME49 strain of T. gondii. This finding enabled us to address the hypothesis that latent toxoplasmosis potentiates disease in the YAC128 mouse model of HD, as these mice are maintained on the FVB/NJ background. Wild-type and HD mice were infected at 2-months of age. During the 10-month follow-up, infection had adverse effects on mice of both genotypes. However, YAC128 HD mice demonstrated specific vulnerability to latent toxoplasmosis, as demonstrated by the presence of increased striatal degeneration, high levels of the blood neurodegeneration marker neurofilament light protein, and elevated brain soluble mHTT. Our studies have uncovered a novel HD-infection interaction in mice that provides insights into the large variability of the human HD phenotype.
