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

Abstract

Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections1,2. Nevertheless, most patients with coronavirus disease 2019 (COVID-19) recover seamlessly without developing ARDS3, suggesting the existence of endogenous pathways to protect the lungs. Since many microRNAs (miRNAs) serve important roles in endogenous regulatory pathways, we pursued functional roles of miRNAs in COVID-19-ARDS. A screen of miRNAs in human alveolar epithelia or mice infected with SARS-CoV-2 identified miR-147 as a lead candidate. Transcriptional analysis implicated hypoxia-inducible factor 1A (HIF1A) in miR-147 induction during alveolar injury or SARS-CoV-2 infection. Functionally, mice with alveolar epithelial deletion of miR-147 showed increased lung injury in response to SARS-CoV-2 infection. mRNA sequencing and subsequent in silico miR-147-target analysis revealed reduced antiviral responses and identified SARS-CoV-2 ORF8 as a direct miR-147 target. Moreover, mice infected with SARS-CoV-2 and treated with miR-147 packaged in DOPC nanoliposomes showed significant protection with enhanced antiviral responses and improved survival. Finally, proof-of-principle studies in patients with COVID-19 highlighted this pathway in human SARS-CoV-2-associated ARDS. Together, our findings identify a previously unrecognized role of miR-147 in lung protection during viral pneumonia by attenuating immune evasion of SARS-CoV-2.