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.