Early Trypanosoma cruzi Infection Triggers mTORC1-Mediated Respiration Increase and Mitochondrial Biogenesis in Human Primary Cardiomyocytes

Abstract

Chagasic chronic cardiomyopathy is one of the most frequent and severe manifestations of Chagas disease, caused by the parasite Trypanosoma cruzi. The pathogenic and biochemical mechanisms responsible for cardiac lesions remain not completely understood, although it is clear that hypertrophy and subsequent heart dilatation is in part caused by the direct infection of cardiomyocytes. In this work, we evaluated the initial response of human cardiomyocytes to T. cruzi infection by transcriptomic profiling. Immediately after infection, cardiomyocytes dramatically change their gene expression patterns, up regulating most of the genes encoding for respiratory chain, oxidative phosphorylation and protein synthesis. We found that these changes correlate with an increase in basal and maximal respiration, as well as in spare respiratory capacity, which is accompanied by mitochondrial biogenesis pgc-1α independent. We also demonstrate that these changes are mediated by mTORC1 and reversed by rapamycin, resembling the molecular mechanisms described for the non-chagasic hypertrophic cardiomyopathy. The results of the present work identify that early during infection, the activation of mTORC1, mitochondrial biogenesis and improvement in oxidative phosphorylation are key biochemical changes that provide new insights into the host response to parasite infection and the pathogenesis of chronic chagasic cardiomyopathy. The finding that this phenotype can be reversed opens a new perspective in the treatment of Chagas disease, through the identification of host targets, and the use of combined parasite and host targeted therapies, in order to prevent chagasic cardiomyopathy.

Differential Modulation of Mouse Heart Gene Expression by Infection With Two Trypanosoma cruzi Strains: A Transcriptome Analysis

“…Experiments in vivo using mouse models during early timepoints, are in consistency with our findings that these genes decrease expression over disease progression (Garg et al, 2003;Vyatkina et al, 2004). Also, studies with cell cultures of human and mouse cardiomyocytes have shown the increase in the expression of such energy metabolism pathways (Shivali et al, 2009;Libisch et al, 2018). Is important to note that such variations might be result of genetic variability of strains or the timing of the T. cruzi infection.…”

Trypanosoma cruzi Modulates PIWI-Interacting RNA Expression in Primary Human Cardiac Myocytes during the Early Phase of Infection

“…Studies using cardiac tissues from patients presenting with Chagasic cardiomyopathy suggest that genes associated with dilated cardiomyopathy and inflammatory responses play a significant role in the onset of Chagasic cardiac hypertrophy [ 14 ]. Additionally, studies have shown that T. cruzi can upregulate the expression of genes involved in extracellular matrix function and mitochondrial energy metabolism, which play a role in the development of cardiac hypertrophy [ 15 , 16 ]. Using primary human cardiomyocytes (PHCMs), our laboratory demonstrated that T. cruzi induced differential expression of fibrogenic genes during the early phase of infection; these genes include JunB, FOS, EGR1, EGR3 and SNAI1 [ 15 ].…”

Transcriptional Studies on Trypanosoma cruzi – Host Cell Interactions: A Complex Puzzle of Variables

“…To exemplify the differences between the host responses to T. cruzi infection given the experiment design, we will focus the analysis on the respiratory chain and oxidative phosphorylation (OXPHOS) responses (Table 2). First, when comparing in vitro-based transcriptomic responses of human primary cardiomyocytes at early times post infection we found, using the Dm28c strain (TcI), upregulation of pathways related to energy metabolism (Libisch et al, 2018), while Udoko et al (2016) using the Tulahuen strain (TcVI) did not found these changes. Concerning in vitro transcriptomic experiments performed in murine (instead of human) primary cardiomyocytes at early time post-infection, Manque et al (Manque et al, 2011), using the Dm28c strain did not found significant changes in pathways related to energy metabolism, while Goldenberg et al with the Brazil strain (TcI) observed a down-regulation of the electron transport activity GO term (Goldenberg et al, 2009), although in this last case the analysis was on late time post infection.…”