Small molecule biomarkers of cardiac Chagas disease progression

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Project summary/abstract The parasite Trypanosoma cruzi is the causative agent of Chagas disease (CD), which affects 5-6 million people worldwide and over 300,000 in the United States alone. 20% to 30% of T. cruzi-infected individuals develop symptomatic disease leading to heart failure, making it an important cause of heart failure in Latin America. There are currently no tools available for clinicians to predict which patients will develop severe disease and which will not. Standard of care in endemic Latin American nations is to treat all infected children; however, there is no consensus on treatment of asymptomatic adults. Current CDC guidelines recommend treating T. cruzi-positive individuals 50 years or younger who do not yet present severe symptoms; treatment is optional for patients over 50 years old due to the high risk of side effects, even though adults age 51 and over represent a quarter of all CD patients. CD treatment regimens are poorly tolerated, with up to 30% of patients failing to complete the full treatment course due to side effects. Treating all infected individuals exposes the ~70% of T. cruzi-infected individuals who were never going to develop clinical manifestations to a dangerous drug for no reason. An outcome-predictive biomarker would help clinicians and their patients weigh treatment risks and benefits, identify high-risk patients for increased monitoring and follow-up, leading to higher patient compliance and treatment completion, while sparing those who are unlikely to develop heart disease unnecessary drug toxicities. Progression biomarkers would also facilitate clinical trials for novel CD therapeutics. Our recent research has shown that the cardiac small molecule profile differs between severe and mild infections in mice and non-human primates. Key differential metabolites include acylcarnitine family members, which are also decreased by infection in the serum, in chronic CD mouse models. Based on this preliminary data, we hypothesize that serum small molecules will predict CD progression in humans. We will apply a combination of targeted and untargeted high-resolution mass spectrometry-based approaches to test this hypothesis, in a clinical cohort of CD patients from Bolivia. First, we will determine whether the circulating acylcarnitine profile differs between patients who will progress to severe disease and non- progressors (aim 1). In parallel, we will apply an untargeted metabolomic strategy on the same serum samples to identify alternative biomarkers, and validate these biomarkers by accurate mass spectrometric quantification in independent samples (aim 2). Jointly, aims 1 and 2 will lead to the identification of high-quality candidate biomarkers. Future long-term work will test the biomarkers identified in this R21 in expanded clinical cohorts and evaluate how these biomarkers change over time. Overall, this work meets a great clinical need, by identifying new prognostic biomarkers for CD that will lead to improved patient management and treatment.