A virus-encoded microRNA contributes to evade innate immune response during SARS-CoV-2 infection

Singh, Meetali; Chazal, Maxime; Quarato, Piergiuseppe; Bourdon, Loan; Malabat, Christophe; Vallet, Thomas; Vignuzzi, Marco; van der Werf, Sylvie; Behillil, Sylvie; Donati, Flora; Sauvonnet, Nathalie; Nigro, Giulia; Bourgine, Maryline; Jouvenet, Nolwenn; Cecere, Germano

SARS-CoV-2 infection results in impaired interferon response in severe COVID-19 patients. However, how SARS-CoV-2 interferes with host immune response is incompletely understood. Here, we sequenced small RNAs from SARS-CoV-2-infected human cells and identified a micro-RNA (miRNA) encoded in a recently evolved region of the viral genome. We show that the virus-encoded miRNA produces two miRNA isoforms in infected cells by the enzyme Dicer and they are loaded into Argonaute proteins. Moreover, the predominant miRNA isoform targets the 3’UTR of interferon-stimulated genes and represses their expression in a miRNA-like fashion. Finally, the two viral miRNA isoforms were detected in nasopharyngeal swabs from COVID-19 patients. We propose that SARS-CoV-2 employs a virus-encoded miRNA to hijack the host miRNA machinery and evade the interferon-mediated immune response.