Comprehensive T. cruzi and auto-antibody profiling in Chagas cardiomyopathy: leveraging phage-display and next-generation sequencing to reassess an old hypothesis

Abstract

Trypanosoma cruzi (T. cruzi) causes Chagas disease. An estimated 6 to 9 million people worldwide are currently infected with T. cruzi and approximately 70 million are at risk of infection. About 30% of individuals infected with T. cruzi develop a fatal dilated cardiomyopathy. The disease has no cure and there are no clinical or epidemiological predictors for directing medical attention to whom, among infected individuals, will develop cardiomyopathy. Although mechanisms leading to cardiomyopathy remain unknown, a line of evidence implicate host (auto)immune response as mediator of disease pathogenicity. Resolving disease mechanism(s) has been hindered by sample availability and by technical issues precluding a comprehensive view of host antibody response. In this application we propose to determine if specific host immune responses are associated/predictive of heart disease development in T. cruzi infection. We will profile sera from Chagas patients with and without cardiomyopathy to identify both T. cruzi epitopes and human autoantibodies and then associate presence and titers of identified antibodies to disease severity and progression. For these studies we will bring together two unique resources that our group and collaborators have been able to assemble: (1) a large collection of blood samples organized by the Brazilian Consortium for Genetics of Chagas Cardiomyopathy, and (2) high throughput antibody profiling technologies (T7-PEP and PLATO) able to comprehensively screen biological samples for the entire range of both human and pathogen proteomes.