Abstract 13092: Regulation of SARS-CoV-2, Viral Entry Proteins ACE2 and TMPRSS2, and Interferon Genes by Host MicroRNAs

Abstract

Introduction: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019, can cause myocardial injury, heart failure, and death. MicroRNAs (miRNAs) have emerged as important regulators of viral pathogenesis, but the impact of host miRNAs on SARS-CoV-2 infectivity remains unknown. Hypothesis: Bioinformatic analysis of host miRNAs targeting the SARS-CoV-2 genome, viral entry proteins ACE2 and TMPRSS2, and their upstream regulators the interferons (IFNs) will reveal high-probability miRNAs that may regulate myocardial injury during SARS-CoV-2 infection. Methods: Using validated bioinformatic prediction algorithms, we generated a prioritized atlas of host miRNAs predicted to bind to SARS-CoV-2 genome, ACE2, TMPRSS2, and IFNs. We validated the biologic plausibility of these binding interactions by investigating their expression in established miRNA profiling datasets from cell lines susceptible or resistant to SARS-CoV-2 infection and in human tissue samples. Results: Phylogenetic analysis of 820 SARS-CoV-2 genomes revealed high homology and, after iterative filtering, 288 predicted binding miRNAs. Overlay of these miRNAs in susceptible and resistant cell lines identified miRNA binders to ORFs (miR-23a (1ab), miR-29a, -29c (1ab, N), miR-151a, -151b (S spike), miR-4707-3p (S spike), miR-298 (5’-UTR), miR-7851-3p (5’-UTR), miR-8075 (5’-UTR)) that may be important for viral infectivity. We also highlight miRNAs predicted to regulate critical host factors during infection including the receptor ACE2 3’-UTR (miR-9-5p, miR-218-5p), the serine protease TMPRSS2 3’-UTR (let-7d-5p, -7e-5p, miR-494-3p, miR-382-3p, miR-181c-5p), and the IFNs such as IFN-α 3’-UTR (miR-361-5p, miR-410-3p). Given the known roles for several of these miRNAs in cardiovascular injury (e.g. miR-23a, -29a, -29c, -494, and let-7), we discuss a framework for further interrogation of these miRNAs in patients and disease-based models. Conclusions: Overall, this study provides insight into potential novel regulatory mechanisms of SARS-CoV-2 by host miRNAs and lays the foundation for future investigation of these miRNAs as potential therapeutic targets or biomarkers for myocardial injury.