Persistent Biofluid Small-Molecule Alterations Induced by Trypanosoma cruzi Infection Are Not Restored by Parasite Elimination.

Chagas disease (CD), caused by Trypanosoma cruzi (T. cruzi) protozoa, is a complicated parasitic illness with inadequate medical measures for diagnosing infection and monitoring treatment success. To address this gap, we analyzed changes in the metabolome of T. cruzi-infected mice via liquid chromatography tandem mass spectrometry of clinically accessible biofluids: saliva, urine, and plasma. Urine was the most indicative of infection status across mouse and parasite genotypes. Metabolites perturbed by infection in urine include kynurenate, acylcarnitines, and threonylcarbamoyladenosine. Based on these results, we sought to implement urine as a tool for the assessment of CD treatment success. Strikingly, it was found that mice with parasite clearance following benznidazole antiparasitic treatment had an overall urine metabolome comparable to that of mice that failed to clear parasites. These results provide a complementary hypothesis to explain clinical trial data in which benznidazole treatment did not improve patient outcomes in late-stage disease, even in patients with successful parasite clearance. Overall, this study provides insights into new small-molecule-based CD diagnostic methods and a new approach to assess functional responses to treatment.

Localized cardiac small molecule trajectories and persistent chemical sequelae in experimental Chagas disease.

Post-infectious conditions present major health burdens but remain poorly understood. In Chagas disease (CD), caused by Trypanosoma cruzi parasites, antiparasitic agents that successfully clear T. cruzi do not always improve clinical outcomes. In this study, we reveal differential small molecule trajectories between cardiac regions during chronic T. cruzi infection, matching with characteristic CD apical aneurysm sites. Incomplete, region-specific, cardiac small molecule restoration is observed in animals treated with the antiparasitic benznidazole. In contrast, superior restoration of the cardiac small molecule profile is observed for a combination treatment of reduced-dose benznidazole plus an immunotherapy, even with less parasite burden reduction. Overall, these results reveal molecular mechanisms of CD treatment based on simultaneous effects on the pathogen and on host small molecule responses, and expand our understanding of clinical treatment failure in CD. This link between infection and subsequent persistent small molecule perturbation broadens our understanding of infectious disease sequelae.

Central role of metabolism in Trypanosoma cruzi tropism and Chagas disease pathogenesis.

Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi parasites. During mammalian infection, T. cruzi alternates between an intracellular stage and extracellular stage. T. cruzi adapts its metabolism to this lifestyle, while also reshaping host metabolic pathways. Such host metabolic adaptations compensate for parasite-induced stress, but may promote parasite survival and proliferation. Recent work has demonstrated that metabolism controls parasite tropism and location of Chagas disease symptoms, and regulates whether infection is mild or severe. Such findings have important translational applications with regards to treatment and diagnostic test development, though further research is needed with regards to in vivo parasite metabolic gene expression, relationship between magnitude of local metabolic perturbation, parasite strain and disease location, and host-parasite-microbiota co-metabolism.