Localized cardiac metabolic trajectories and post-infectious metabolic sequelae in experimental Chagas disease

Abstract

Post-infectious conditions, where clinical symptoms fail to resolve even after pathogen clearance, present major health burdens. However, the mechanisms involved remain poorly understood. In Chagas disease (CD), caused by the parasite Trypanosoma cruzi, antiparasitic agents can clear T. cruzi but late-stage treatment does not improve clinical cardiac outcomes. In this study, we revealed differential metabolic trajectories of cardiac regions during T. cruzi infection, matching sites of clinical symptoms. Incomplete, region-specific, cardiac metabolic restoration was observed in animals treated with the antiparasitic benznidazole, even though parasites were successfully cleared. In contrast, superior metabolic restoration was observed for a combination treatment of reduced-dose benznidazole plus an immunotherapy (Tc24-C4 T. cruzi flagellar protein and TLR4 agonist adjuvant), even though parasite burden reduction was lower. Overall, these results provide a mechanism to explain prior clinical treatment failures in CD and to test novel candidate treatment regimens. More broadly, our results demonstrate a link between persistent metabolic perturbation and post-infectious conditions, with broad implications for our understanding of post-infectious disease sequelae.

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

“…This could be due to the use of different mouse and parasite strains, but may also reflect the lack of improvements of functional and survival outcomes in late-stage patient treatment, even in cases of parasitological cure, and the disconnect between parasite burden and symptomatic vs asymptomatic chronic infection . Importantly, our urine results concur with analysis of cardiac tissue in an independent infection model, which likewise showed only minor and incomplete metabolic restoration and functional restoration 56 days postbenznidazole treatment, even with successful parasite elimination . As such, our method could represent a quick and noninvasive method to identify compounds with superior efficacy to benznidazole though this will need to be validated in additional animal models.…”

“…Given the relationship between immunity and metabolism (e.g., ref ), and our prior work demonstrating persistent immunological dysfunction after benznidazole treatment, in association with perturbed cardiac metabolism that is improved by an immunomodulating therapeutic, some of these biomarkers may be a reflection of immune signaling. It will be important to assess their specificity to CD as part of their continued development.…”

“…Interestingly, acylcarnitines were decreased by chronic CD in heart tissue in C3H/HeJ mice but increased in acute stage infection in the gastrointestinal tract 51,52 and in the chronic stage in the heart of BALB/c mice. 56 Acylcarnitine metabolism has been causally linked to cardiac metabolism and disease severity in acute T. cruzi infection in mouse models. 52 Lizardo et al also identified these classes of molecules as perturbed in the serum by chronic T. cruzi infection in mouse models.…”

“…Acylcarnitines have already been linked to CD in both heart tissue and the circulation. ,− Our study identified CAR 14:3;O as significantly increased in the urine of males at weeks 4 and 10 postinfection in our validation cohort (Table and Figure S5). Interestingly, acylcarnitines were decreased by chronic CD in heart tissue in C3H/HeJ mice but increased in acute stage infection in the gastrointestinal tract , and in the chronic stage in the heart of BALB/c mice . Acylcarnitine metabolism has been causally linked to cardiac metabolism and disease severity in acute T.…”

“…One limitation is that we assessed metabolic restoration only at 35 days posttreatment. It is possible that metabolism gradually improves over time though incomplete metabolic restoration was also observed in heart tissue 56 days posttreatment . A study of CD patients treated with the other antiparasitic nifurtimox showed restoration of many but not all metabolic perturbations up to three years after treatment .…”