Abstract
Chagas disease (CD) is a parasitic disease caused by Trypanosoma cruzi protozoa, presenting with cardiomyopathy, megaesophagus, and/or megacolon. To determine the mechanisms of gastrointestinal (GI) CD tissue tropism, we systematically characterized the spatial localization of infection-induced metabolic and microbiome alterations, in a mouse model of CD. Notably, the impact of the transition between acute and persistent infection differed between tissue sites, with sustained large-scale effects of infection in the esophagus and large intestine, providing a potential mechanism for the tropism of CD within the GI tract. Infection affected acylcarnitine metabolism; carnitine supplementation prevented acute-stage CD mortality without affecting parasite burden by mitigating infection-induced metabolic disturbances and reducing cardiac strain. Overall, results identified a previously-unknown mechanism of disease tolerance in CD, with potential for new therapeutic regimen development. More broadly, results highlight the potential of spatially resolved metabolomics to provide insight into disease pathogenesis and infectious disease drug development.
Highlights
Chagas disease (CD), known as American trypanosomiasis, is a neglected tropical disease endemic in Latin America
We identified specific small molecules correlated with cardiac parasite tropism (6)
While parasite persistence is required for progression to chronic CD, only a minority of infected patients progress to symptomatic disease, and parasite load does not fully predict disease severity (1)
Summary
Chagas disease (CD), known as American trypanosomiasis, is a neglected tropical disease endemic in Latin America. Infected individuals pass first through an acute disease stage, usually asymptomatic, and to a chronic asymptomatic (indeterminate) stage that can last for decades. Thirty to 40% of infected individuals progress from indeterminate to determinate (symptomatic) chronic CD, 20 to 30% with cardiovascular complications (heart failure, arrhythmias, and thromboembolism) and 10 to 15% with gastrointestinal (GI) symptoms (megaesophagus and megacolon) (1). Recent studies using bioluminescent parasites in mouse models have shown that specific sites in the GI tract are parasite reservoirs in chronic CD and may be major contributors to cardiac symptom development, after treatment failure (2, 3). There is, a strong need to improve our understanding of the interaction between T. cruzi and the GI tract, both to clarify mechanisms of GI CD pathogenesis and to define GI factors contributing to cardiac CD, leading to new treatment strategies
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