Spatially divergent metabolic impact of experimental toxoplasmosis: immunological and microbial correlates

Maladaptive host metabolic responses to infection are emerging as major determinants of infectious disease pathogenesis. However, the factors regulating these metabolic changes within tissues remain poorly understood. In this study, we used toxoplasmosis, as a prototypical example of a disease regulated by strong type I immune responses, to assess the relative roles of current local parasite burden, local tissue inflammation, and the microbiome in shaping local tissue metabolism during acute and chronic infections. Toxoplasmosis is a zoonotic disease caused by the parasite Toxoplasma gondii . This protozoan infects the small intestine and then disseminates broadly in the acute stage of infection, before establishing chronic infection in the skeletal muscle, cardiac muscle, and brain. We compared metabolism in 11 sampling sites in C57BL/6 mice during the acute and chronic stages of T. gondii infection. Strikingly, major spatial mismatches were observed between metabolic perturbation and local parasite burden at the time of sample collection for both disease stages. By contrast, a stronger association with indicators of active type I immune responses was observed, indicating a tighter relationship between metabolic perturbation and local immunity than with local parasite burden. Loss of signaling through the IL1 receptor in IL1R knockout mice was associated with reduced metabolic impact of infection. In addition, we observed significant changes in microbiota composition with infection and candidate microbial origins for multiple metabolites impacted by infection. These findings highlight the metabolic consequences of toxoplasmosis across different organs and potential regulators.

IMPORTANCE

Inflammation is a major driver of tissue perturbation. However, the signals driving these changes on a tissue-intrinsic and molecular level are poorly understood. This study evaluated tissue-specific metabolic perturbations across 11 sampling sites following systemic murine infection with the parasite Toxoplasma gondii . Results revealed relationships between differential metabolite enrichment and variables, including inflammatory signals, pathogen burden, and commensal microbial communities. These data will inform hypotheses about the signals driving specific metabolic adaptation in acute and chronic protozoan infection, with broader implications for infection and inflammation in general.