Molecular mechanisms of Trypanosoma cruzi induced colon pathogenesis

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Project Summary The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical disease which causes severe morbidity, mortality, and economic burden in afflicted individuals. The disease, originally endemic in Latin American countries, has now become a new global health problem in all major economically advanced countries due to modern globalization. About 30% of T. cruzi infected individuals eventually present with cardiac, gastrointestinal tract and/or neurological disorders or a combination thereof. Megacolon, one of Chagas disease major pathologies, is accompanied by an enlarged, fibrotic gastrointestinal tract and GI motility disorders. The mechanisms through which T. cruzi infection causes cardiac, gastrointestinal and neurological disorders in afflicted individuals remains under investigation. The objective of this proposal is to decipher the molecular mechanisms dysregulated by T. cruzi during early infection that contribute to megacolon pathology. The hippo signaling pathway has been identified as a contributor to fibrotic disease across tissue types. Activation of downstream hippo effector molecule YAP initiates transcription of fibrotic genes. We recently showed that T. cruzi activates YAP nuclear translation during the early phase of infection of heart endothelial cells. Thombospondin-1 (TSP-1) was previously shown to be upregulated by the parasite in order to facilitate infection. Knockout of TSP-1 in heart endothelial cells decreased YAP mean fluorescence intensity within the nucleus, indicating that TSP-1 actively interacts with the hippo signaling pathway during T. cruzi infection. PIWI-interacting RNAs (piRNAs), a class of small noncoding RNAs, contribute to gastrointestinal diseases such as gastric cancer, colon cancer, and colorectal cancer. We recently showed that piRNAs can target and regulate genes involved in T. cruzi pathogenesis, such as TGFB1, FOS, and NFATC2. However, the role of piRNAs have not been investigated in colon cells during T. cruzi infection. Based on these observations, we hypothesize that the parasite dysregulates the hippo signaling pathway and piRNAs during the early phase of infection. The hypothesis will be evaluated with the following specific aims: (1) Evaluate the dysregulation of hippo signaling pathway during early phase of T. cruzi infection and (2) Asses the role of piRNAs and PIWIL proteins in the regulation of downstream profibrotic genes during the early phase of infection. This project is significant because it will: identify the role of hippo signaling during T. cruzi infection of colon cells; delineate TSP-1 and hippo signaling interplay during parasite infection; characterize the functional roles of PIWIL proteins and piRNAs shown to be increased during infection using primary human colon epithelial and smooth muscle cells. During the fellowship training period, I will be able to solidify and gain new technical skills, prepare manuscripts, and participate in career developing activities such as scientific communication, scientific writing, and teaching. Meharry Medical College and Meharry-Vanderbilt alliance provide access to equipment for this project.