Untargeted metabolomics reveals L-Lysine depletion as a host-directed therapeutic target in Toxoplasma gondii infection.

Toxoplasmosis is a widespread zoonotic disease causing severe outcomes in immunocompromised individuals and during pregnancy. Current therapeutic options target actively replicating stages of the parasite and show limited efficacy against chronic infection, underscoring the need for complementary therapeutic strategies. While efforts have largely focused on on eliminating the parasite, host-directed strategies aimed at enhancing disease tolerance and preserving tissue integrity remain comparatively underexplored. In this study, we used untargeted serum metabolomics to characterize host metabolic responses to acute and chronic Toxoplasma gondii (T. gondii) infection in a murine model. Our analysis revealed extensive metabolic remodeling during infection, with prominent perturbations in lipid metabolism and amino acid pathways. Among the metabolites most significantly depleted during infection was the essential amino acid L-lysine. We evaluated the impact of L-lysine supplementation on disease outcomes in vivo. L-lysine supplementation was associated with improved survival and reduced tissue pathology during acute and chronic infection. Supplemented mice exhibited reduced inflammatory cytokine dysregulation and lower tissue parasite burdens, effects that are consistent with enhanced host resilience rather than direct antiparasitic activity. These findings identify L-lysine depletion as a metabolic feature of T. gondii infection and demonstrate that its supplementation confers protective benefits in the host. Our study highlights the value of metabolomics-guided approaches for uncovering host metabolic vulnerabilities and supports the concept of L-lysine supplementation as a host-directed adjunctive intervention to mitigate pathology during toxoplasmosis.