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Published on: January 21, 2022
Localized cardiac metabolic trajectories and post-infectious metabolic sequelae in experimental Chagas disease
Zongyuan Liu1,2, Rebecca Ulrich2,3, April L Kendricks4
1Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, United States of America.
Insights
Post-infectious conditions like Chagas disease (CD) persist after pathogen clearance. Novel combination therapy improves cardiac metabolic restoration more than standard antiparasitic treatment alone.
Area of Science:
- Cardiovascular Research
- Infectious Diseases
- Metabolic Medicine
Background:
- Post-infectious conditions, including Chagas disease (CD), present significant health challenges due to unresolved symptoms despite pathogen clearance.
- Current antiparasitic treatments for CD effectively clear *Trypanosoma cruzi* but fail to improve cardiac outcomes in late-stage disease, indicating a gap in understanding disease mechanisms.
Approach:
- Investigated differential metabolic trajectories in cardiac regions during *T. cruzi* infection and assessed metabolic restoration following benznidazole treatment.
- Evaluated a combination therapy of reduced-dose benznidazole with immunotherapy (Tc24-C4 *T. cruzi* flagellar protein and TLR4 agonist adjuvant) for metabolic restoration.
Key Points:
- Cardiac metabolic alterations were region-specific during *T. cruzi* infection, correlating with clinical symptoms.
- Benznidazole monotherapy resulted in incomplete, region-specific cardiac metabolic restoration, even with successful parasite clearance.
- Combination therapy demonstrated superior metabolic restoration compared to benznidazole alone, despite lower parasite burden reduction.
Conclusions:
- Persistent metabolic perturbation is linked to post-infectious sequelae, offering a mechanistic explanation for treatment failures in Chagas disease.
- The findings support novel therapeutic strategies combining antiparasitic and immunotherapies for improved outcomes in post-infectious conditions.
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.
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