HIF-dependent induction of alveolar miR-147b dampens SARS-CoV-2 immune evasion 3751
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)
Authors
- Holger K. Eltzschig (ORCID: https://orcid.org/0000-0002-5676-6473)
- Cristian Rodriguez‐Aguayo (ORCID: https://orcid.org/0000-0002-7880-7723)
- Xuping Xie (ORCID: https://orcid.org/0000-0003-0918-016X)
- Katherine Figarella (ORCID: https://orcid.org/0000-0003-3305-9167)
- Cheng-Yen Chang (ORCID: https://orcid.org/0000-0002-3943-3044)
- Gabriel Lopez‐Berestein
- Agnieszka Czopik (ORCID: https://orcid.org/0009-0000-7179-7537)
- Francesca Polverino (ORCID: https://orcid.org/0000-0001-9686-5698)
- Farrah Kheradmand (ORCID: https://orcid.org/0000-0001-5343-103X)
- Pei‐Yong Shi (ORCID: https://orcid.org/0000-0001-5553-1616)
- Harry Karmouty‐Quintana (ORCID: https://orcid.org/0000-0003-4753-9823)
- Yazhen Hu (ORCID: https://orcid.org/0009-0008-2260-3650)
- Oleg Makarevich (ORCID: https://orcid.org/0000-0003-2061-2285)
- Wei Ruan (ORCID: https://orcid.org/0000-0002-2718-7923)
- Paola Amero (ORCID: https://orcid.org/0000-0002-7503-0381)
- Paul Potnuru (ORCID: https://orcid.org/0000-0003-4359-5342)
- Selanere S. Mangala (ORCID: https://orcid.org/0009-0004-1581-3781)
- Ji-Eun Kim (ORCID: https://orcid.org/0000-0003-0092-2147)
- Yanyu Wang (ORCID: https://orcid.org/0000-0003-3365-3262)
- Xiaoyi Yuan (ORCID: https://orcid.org/0009-0002-4496-7312)
- Tingting Mills (ORCID: https://orcid.org/0000-0002-6041-4788)
- Anil K. Sood (ORCID: https://orcid.org/0000-0003-4242-1762)
- George W. Williams (ORCID: https://orcid.org/0000-0001-9079-610X)
- Thu Ha Tran
Institutions
- The University of Texas Health Science Center (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- The Journal of Immunology
- Published
- 2025-11-01
- DOI
- https://doi.org/10.1093/jimmun/vkaf283.1516
- Primary Topic
- COVID-19 Clinical Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Government of Ontario
- Brock University
- National Institutes of Health
- Health Science Center, University of North Texas
- Natural Sciences and Engineering Research Council of Canada
- National Institute on Aging
- National Institute on Minority Health and Health Disparities