Parasitic infections such as leishmaniasis induce a cascade of host physiological responses, including
metabolic and immunological changes. Infection with Leishmania major parasites causes cutaneous
leishmaniasis in humans, a neglected tropical disease that is difficult to manage. To understand the
determinants of pathology, we studied L. major infection in two mouse models: the self-healing
C57BL/6 strain and the nonhealing BALB/c strain. Metabolic profiling of urine, plasma, and feces via
proton NMR spectroscopy was performed to discover parasite-specific imprints on global host
metabolism. Plasma cytokine status and fecal microbiome were also characterized as additional metrics
of the host response to infection. Results demonstrated differences in glucose and lipid metabolism,
distinctive immunological phenotypes, and shifts in microbial composition between the two models.
We present a novel approach to integrate such metrics using correlation network analyses, whereby
self-healing mice demonstrated an orchestrated interaction between the biological measures shortly
after infection. In contrast, the response observed in nonhealing mice was delayed and fragmented. Our
study suggests that trans-system communication across host metabolism, the innate immune system,
and gut microbiome is key for a successful host response to L. major and provides a new concept,
potentially translatable to other diseases.