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

Abstract

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.

Small molecule biomarkers predictive of Chagas disease progression

“…For PRM data analysis, collected data from the validation cohorts were analyzed through Skyline software (version 23.1) with parameters as in 27…”

“…For PRM data analysis, collected data from the validation cohorts were analyzed through Skyline software (version 23.1) with parameters as in 27 . The exported peak areas were normalized by the peak area of the internal standard ( m/z 311.0801 for positive mode and m/z 309.0656 for negative mode).…”

“…in human subjects and mouse models 27,28,29 . The level of cardiac acylcarnitines and glycerophosphocholines were correlated with markers of cardiac inflammation and fibrosis 30 .…”

“…Serum and urine metabolites have been identified as indicators of T. cruzi infection status in human subjects and mouse models 27,28,29 . The level of cardiac acylcarnitines and glycerophosphocholines were correlated with markers of cardiac inflammation and fibrosis 30 .…”