Examination Date

Spring 3-10-2025

Degree

Dissertation

Degree Program

Microbiology, Immunology and Parasitology

Abstract

Chagas disease remains a significant global health challenge due to persistent vector transmission, increasing non-vector transmission, and limited therapeutic options. Chronic Chagas cardiomyopathy is a leading cause of morbidity and mortality, yet the underlying mechanisms remain poorly understood. Since the initial discovery of Trypanosoma cruzi more than 100 years ago Chagas disease research focus has often been placed on investigating the contribution of cardiomyocytes and cardiac fibroblasts, but not cardiac endothelial cells, on Chagas pathogenesis, leaving a significant gap in understanding of the role of vascular dysfunction in disease progression. Additionally, distinct challenges exist with current methods used to accurately model vascular dysfunction during Chagas disease in vitro, severely limiting the development of new therapeutic options for Chagas symptom management. This dissertation investigates host-parasite interactions contributing to Trypanosoma cruzi-induced endothelial cell dysfunction and cardiac remodeling. We develop an improved in vitro 3D model of cardiac infection that includes endothelial cells, and we present data that supports the use of this model in Chagas disease research. We present data to demonstrate morphological and functional changes in cardiac endothelial cells during infection and propose a previously unrecognized link between enhanced endothelial migration and dysfunctional angiogenesis that occurs in chronic Chagas cardiomyopathy. We present data that does not support cardiac microvasculature as being a contributor to cardiac fibrosis during infection, further cementing the role of cardiac fibroblasts in fibrotic Chagas pathogenesis. This dissertation demonstrates the importance of strengthening our understanding of T. cruzi-induced endothelial cell dysfunction for the development of novel therapeutic targets to combat cardiac vascular remodeling in Chagas disease.

Additional Files
Gisclair, Lyndsey - Dissertation Report Form.pdf (104 kB)
Dissertation Report Form
Download

Share

COinS