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. While research has focused on parasite-directed therapies, host-directed strategies to enhance tolerance and preserve tissue integrity remain underexplored. In this study, we analyzed untargeted serum metabolomics data to identify host metabolic alterations during acute and chronic Toxoplasma gondii (T. gondii) infection in a murine model. Analysis of metabolomic data revealed widespread infection-associated metabolic remodeling, with consistent perturbations in lipid metabolism and amino acid pathways. Among the metabolites most robustly 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 a trend toward improved survival and reduced tissue pathology during both acute and chronic infection. Supplemented mice also 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 measurable host-protective benefits. 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.