Cellular microRNAs target SARS-CoV-2 spike protein and restrict viral replication

MicroRNAs (miRNAs) regulate gene expression posttranscriptionally and are implicated in viral replication and host tropism. miRNAs can impact the viruses either by directly interacting with the viral genome or modulating host factors. Although many miRNAs have predicted binding sites in the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral RNA genome, little experimental validation has been done. We first identified 492 miRNAs that have binding site(s) on the spike (S) viral RNA by a bioinformatics prediction. We then validated the selected 39 miRNAs by examining S-protein levels after coexpressing the S-protein and a miRNA into the cells. Seven miRNAs were found to reduce the S-protein levels by more than 50%. Among them, miR-15a, miR-153, miR-298, miR-508, miR-1909, and miR-3130 also significantly reduced SARS-CoV-2 viral replication. SARS-CoV-2 infection decreased the expression levels of miR-298, miR-497, miR-508, miR-1909, and miR-3130, but had no significant effects on miR-15a and miR-153 levels. Intriguingly, the targeting sequences of these miRNAs on the S viral RNA showed sequence conservation among the variants of concern. Our results suggest that these miRNAs elicit effective antiviral defense against SARS-CoV-2 by modulating S-protein expression and are likely targeting all the variants. Thus, the data signify the therapeutic potential of miRNA-based therapy for SARS-CoV-2 infections.NEW & NOTEWORTHY MicroRNAs can impact viruses either by directly interacting with the virus genome or by modulating host factors. We identified that cellular miRNAs regulate effective antiviral defense against SARS-CoV-2 via modulating spike protein expression, which may offer a potential candidate for antiviral therapy.