AUTHOR=Venturini Gabriela , Alvim Juliana M. , Padilha Kallyandra , Toepfer Christopher N. , Gorham Joshua M. , Wasson Lauren K. , Biagi Diogo , Schenkman Sergio , Carvalho Valdemir M. , Salgueiro Jessica S. , Cardozo Karina H. M. , Krieger Jose E. , Pereira Alexandre C. , Seidman Jonathan G. , Seidman Christine E. 

TITLE=Cardiomyocyte infection by Trypanosoma cruzi promotes innate immune response and glycolysis activation

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 13 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2023.1098457

DOI=10.3389/fcimb.2023.1098457

ISSN=2235-2988

ABSTRACT=Chagas cardiomyopathy, a disease caused by Trypanosoma cruzi (T. cruzi) infection, is a major contributor to heart failure in Latin America. However, there are significant gaps in our understanding of the mechanism of infection in human cardiomyocytes, the pathways activated during the acute phase of the disease, and the molecular changes that lead to the progression of cardiomyopathy. To investigate the effects of T. cruzi on human cardiomyocytes during infection, we infected induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) with the parasite and analyzed cellular, molecular, and metabolic responses at 3 hours, 24 hours, and 48 hours post infection (hpi) using transcriptomics (RNAseq), proteomics (LC-MS), and metabolomics (GC-MS and Seahorse) analysis. The omics data showed a rapid increase in genes and proteins related to activated innate and adaptive immune systems and pathways in cardiomyocytes, such as components of interferon alpha and gamma, HIF-1α signaling, and glycolysis, resembling prototypic responses in pathogen-activated immune cells. Infection also caused an activation of glycolysis that was dependent on HIF-1α signaling. Using gene editing and pharmacological inhibitors, we found that T. cruzi uptake was mediated in part by the glucose-facilitated transporter GLUT4 and that the attenuation of glycolysis, HIF-1α activation, or GLUT4 expression decreased T. cruzi infection. In contrast, pre-activation of pro-inflammatory immune responses with LPS resulted in increased infection rates. These findings suggest that T. cruzi exploits a HIF-1α-dependent, cardiomyocyte-intrinsic stress-response activation of glycolysis to promote intracellular infection and replication, while impairing cardiomyocyte physiology and function through the use of GLUT4.