163 - Early Perturbations in Mitochondrial Metabolism and Bioenergetics Exerted by Trypanosoma cruzi Infection in Human Cardiomyocytes

Abstract

Chagas’ disease is a zoonotic disease caused by Trypanosoma cruzi infection that is endemic in Mexico, Central and South America. Usually, the disease is transmitted by a triatomine vector and domestic and wild mammals that serve as reservoirs for this parasitic protozoan. However, due to increased immigration, individuals with the disease have been identified in developed countries like the USA, Canada and Europe, increasing the possibility of secondary transmission routes of T. cruzi via organ transplantation, blood transfusions and maternal-fetal transmission. The clinical course of the disease is divided into the acute and chronic phases. While the acute infection is mildly asymptomatic and often misdiagnosed, the chronic phase usually manifests as cardiomyopathy with a wide spectrum of manifestations, ranging from minor myocardium involvement to left ventricular (LV) systolic dysfunction, dilated cardiomyopathy, arrhythmias, thromboembolic events, and terminal cardiac failure. Interestingly, because chagasic hearts are virtually free of parasites, and the etiology of chronic Chagas disease remains under heavy discussion. The B and T cell immunity in combination with mitochondrial dysfunction, inflammatory cytokines/chemokines, and oxidative stress are the hallmark of the disease. In this work, we aimed to elucidate the early metabolic perturbations exerted by T. cruzi (Sylvio X10) infection in AC16 human cardiomyocytes. In addition, we also examined the role of innate immunity by co-treating cells with pro-inflammatory proteins and cytokines known to have a role in the infection process like IFN-γ, TNF-α and IL-6. Early changes in metabolism and mitochondrial bioenergetics were assessed in real time with a Seahorse XFe24 Extracellular Flux Analyzer. We found that T. cruzi infection alone, was not enough to induce significant changes in mitochondrial metabolism and bioenergetics and to increase ROS generation in human cardiomyocytes. However, T. cruzi infection in combination with IFN-γ, TNF-α and IL-6 exerted a drastic effect in cardiomyocyte mitochondrial bioenergetics and ROS production, suggesting that innate immunity plays a key role in Chagas-induced cardiomyopathy.