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

Zongyuan Liu, Rebecca Ulrich vonBargen, April L. Kendricks, Kate Wheeler, Ana Carolina Leão, Krithivasan Sankaranarayanan, Danya A. Dean, Shelley S. Kane, Ekram Hossain, Jeroen Pollet, Maria Elena Bottazzi, Peter J. Hotez, Kathryn M. Jones () and Laura-Isobel McCall ()
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Zongyuan Liu: University of Oklahoma
Rebecca Ulrich vonBargen: University of Oklahoma
April L. Kendricks: Southern Star Medical Research Institute
Kate Wheeler: University of Oklahoma
Ana Carolina Leão: Baylor College of Medicine
Krithivasan Sankaranarayanan: University of Oklahoma
Danya A. Dean: University of Oklahoma
Shelley S. Kane: University of Oklahoma
Ekram Hossain: University of Oklahoma
Jeroen Pollet: Baylor College of Medicine
Maria Elena Bottazzi: Baylor College of Medicine
Peter J. Hotez: Baylor College of Medicine
Kathryn M. Jones: Baylor College of Medicine
Laura-Isobel McCall: University of Oklahoma

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42247-w

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