Sars-Cov-2 Infection Of The Human Heart Governs Intracardiac Innate Immune Response.

Abstract Human coronavirus, hCoV-19 (SARS-CoV-2) is associated with pneumonia, severe systemic disease and, in fatal cases, a high prevalence of cardiac dysfunction. Cellular entry requires a cell-surface receptor, angiotensin-converting enzyme 2 (ACE2), and activation of the spike protein by host proteases, including TMPRSS2 and cathepsins. Cardiac toxicity is a serious cause of morbidity and mortality from SARS-CoV-2 with chronic sequelae reducing cardiac function in many survivors. We determined mRNA expression for genes related to SARS-Cov-2 infection in iPSC-derived cardiac myocytes treated with the widely used chemotherapeutic, Doxorubicin (DOX). DOX induced expression of TMPSS2, but not Ace2 or Furin, 4- to 5-fold. Further, DOX treatment enhanced expression of cathepsins A, B and F between 1.2-1.5 fold. Overall these changes promote an environment of enhanced SARS-CoV-2 susceptibility in the myocardium placing cancer patients on DOX therapy at increased risk of cardiac damage. To further characterize the effects of SARS-CoV-2 on the myocardium we examined the local spatial gene expression response in human post-mortem cardiac samples. A genome wide (1,864 genes) and matching proteome analysis on SARS-CoV-2 infected myocardium was conducted using Digital spatial profiling (DSP) (NanoString GeoMxTM). RNAscopeTM, a sensitive form of fluorescence in situ hybridization (FISH), identified SARS-CoV-2 spike RNA in cells enriched for ACE2 and TMPRSS2. Immunohistochemistry on serial sections identified the SARS-CoV-2 spike protein in both myocyte (desmin+) and monocyte (CD45+) populations suggesting multiple targets for viral infection in the myocardium. SCANscopeTM was used to determine the effects of SARS-CoV-2 on cardiac gene. Probes directed to the spike protein were used to identify regions of interest (ROI) for SARS-CoV-2-infection. Unsupervised principal component analysis (PCA) of the differentially expressed gene transcripts separated gene expression of SARS-CoV-2 ROI from control ROI areas in the same patient and was distinct from the PCA of normal myocardium control ROI. PCA of the SARS-CoV-2-associated gene expression of the ROI from male vs. female myocardium identified distinct gender-related gene expression patterns. Further, PCA based on SARS-Cov-2 spike RNA abundance correlated with induction of innate and acquired immunity signaling in the myocardial cells. Moreover, gene ontology (Reactome) analysis of SARS-CoV-2 infected regions of the myocardium displayed characteristic signatures indicating enhanced apoptosis and autophagy, chromatin remodeling and reduced DNA repair, and reduced oxidoreductase activity in regions of SARS-CoV-2 infection compared to uninfected myocardium. These data probe the underlying molecular mechanisms that enhance the risk of death from SARS-CoV-2 for cancer patients and the cardiac remodeling that results in death for many patients with COVID-19. Citation Format: Anthony W. Ashton, Liang Zhang, Yan Liang, Prajan Divakar, Carolos Cordon-Cardo, Richard G. Pestell. SARS-CoV-2 infection of the human heart governs intracardiac innate immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 705.