Saturday, May 4, 2024
5/4/2024
PROJECT SUMMARY/ABSTRACT Chronic Chagas cardiomyopathy (CCC) is a devastating disease that develops in 30-40% of individuals decades after initial infection with Trypanosoma cruzi, resulting in heart failure, cardiac arrhythmia, stroke, pulmonary embolism, and sudden cardiac death. Currently, there is no effective treatment for CCC, there is no way to predict which patients will go on to develop CCC, and the mechanisms that underly the disease progression are very poorly understood. A better understanding of CCC pathogenesis is therefore urgently needed to develop novel treatment strategies and allow for risk stratification of patients in need of personalized interventions. A compelling hypothesis to explain the pathogenesis of CCC centers around a hyperinflammatory immune response that results in excessive cardiac damage over time. This study focuses on investigating how B cells and their interactions with other cells can potentiate proinflammatory and autoimmune responses to mediate the cardiac pathology seen in CCC. In the first aim, I will use a combination of high-throughput single- cell RNA sequencing (scRNAseq) and spatial transcriptomics of human CCC samples to characterize the immune pathways mediating CCC. Using scRNAseq on peripheral blood mononuclear cells from a longitudinal cohort of patients that are known to develop CCC, I will characterize immune cell alterations that precede CCC at a high resolution, potentially revealing early processes that mediate disease progression. Spatial transcriptomics will be employed on end-stage human CCC heart tissue to determine the spatial association of proinflammatory gene expression with regions of cardiac damage. This will help characterize the immune cell subtypes and pathways that are most likely mediating direct tissue damage in human Chagas disease. Together, these data will highlight potential therapeutic targets for both early and advanced CCC. The analyses of these high-throughput sequencing experiments will have a strong focus on evaluating pro-inflammatory immune cells, including B cells, and their signaling pathways. The second aim of this project seeks to determine whether B cell depletion can provide a therapeutic benefit in a murine model of CCC. B cells will be depleted in two different groups: 1) before cardiac manifestations develop, to evaluate the feasibility of immunotherapy for halting disease progression; and 2) after cardiac manifestations have occurred, to evaluate whether targeted B cell depletion can provide a therapeutic benefit in the advanced form of the disease. Overall, the proposed study will transform our understanding of the immunologic mechanisms underlying CCC pathogenesis. Long term, this work can serve to change the way in which we manage CCC, allowing us to ultimately treat Chagas disease as an immunologic disorder rather than an infectious one. Long term, this work will serve to inform strategies for diagnosis, prevention, and management of this important cardiac disease.
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