HIF-dependent induction of alveolar miR-147b dampens SARS-CoV-2 immune evasion 3751

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Abstract Description Acute respiratory distress syndrome (ARDS) causes morbidity and mortality during SARS-CoV-2 infections. Nevertheless, most patients with SARS-CoV-2 infection recover seamlessly without developing ARDS. Here, we hypothesized a functional role of microRNAs (miRNAs) in endogenous lung protection during SARS-CoV-2-associated ARDS. Screening studies identified miR-147b (hsa-miR-147b-3p or mmu-miR-147-3p) as the lead candidate during murine and human SARS-CoV-2 infections. Functional molecular studies implicate hypoxia-inducible factor 1A (HIF1A) in miR-147b induction. Subsequent loss-and-gain-of-function studies revealed a protective role of alveolar-expressed miR-147b during murine SARS-CoV-2-associated ARDS. Proof-of-principle studies in patients also implicate this pathway during SARS-CoV-2 infection. Finally, we identified SARS-CoV-2 ORF8 as a direct miR-147b target, and silent mutation of the viral miR-147b-binding site within ORF-8 abolished the observed protection. Together, our findings identify a previously unrecognized role of miR-147b in attenuating SARS-CoV-2-associated lung disease by targeting the viral genome. Funding Sources R01HL154720, R01DK122796, R01HL133900, R01HL155950, R01HL169519, T32GM135118; Department of Defense Grant W81XWH2110032; Parker B. Francis Fellowship; American Lung Association Catalyst Award CA-622265. Topic Categories Viral Immunology (VIR)

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