{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T01:45:21Z","timestamp":1782783921188,"version":"3.54.5"},"reference-count":63,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EU within NextGenerationEU\u2014Mission 4 Component 1\u2014MUR PNRR INFACT\u2014One Health Basic and Translational Research Actions addressing Unmet Needs on Emerging Infectious Diseases","award":["PE00000007\u2014CUP B43C22000690006"],"award-info":[{"award-number":["PE00000007\u2014CUP B43C22000690006"]}]},{"name":"University of Campania \u201cL. Vanvitelli\u201d"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Host microRNAs (miRNAs) are widely proposed as innate antiviral effectors against SARS-CoV-2, yet whether they actually restrict infection in lung epithelial cells remains unresolved. Two of the most-cited candidates, miR-29a-3p and miR-15b-5p, are predicted to bind both the viral genome and key entry\/trafficking factors such as Furin and ATG9A, but functional evidence is fragmented and often contradictory. Here, we put both miRNAs to the test in human Calu-3 cells infected with the SARS-CoV-2 Beta and Omicron BA.1 variants, using parallel gain- and loss-of-function strategies coupled to RT-qPCR of viral and cellular transcripts and back-titration of infectious progeny on VeroE6\/TMPRSS2 cells. Both miRNAs transiently suppressed viral gene expression at 6 hpi, but this early dampening was followed by a marked transcript rebound at 24 hpi, especially for Omicron, with virtually no impact on total extracellular viral RNA. More strikingly, miR-15b modulation enhanced infectious virus output during Beta infection, and miR-29a overexpression boosted Omicron BA.1 infectivity, while Furin, ATG9A, AKT3, and TFEB showed only modest, condition-dependent shifts. Rather than acting as clean antiviral effectors, miR-29a and miR-15b emerge as context-dependent modulators that can paradoxically favor SARS-CoV-2 replication\u2014a cautionary signal for miRNA-based antiviral strategies.<\/jats:p>","DOI":"10.3390\/ijms27135847","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:55:11Z","timestamp":1782780911000},"page":"5847","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["miR-29a and miR-15b Modulate SARS-CoV-2 Beta and Omicron Infection in Human Lung Epithelial Cells"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0185-3147","authenticated-orcid":false,"given":"Elena","family":"Criscuolo","sequence":"first","affiliation":[{"name":"Laboratory of Microbiology and Virology, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0405-3807","authenticated-orcid":false,"given":"Nicola","family":"Mosca","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania \u00abL. Vanvitelli\u00bb, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4337-5024","authenticated-orcid":false,"given":"Benedetta","family":"Giuliani","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Virology, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0295-7941","authenticated-orcid":false,"given":"Matteo","family":"Castelli","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Virology, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armando","family":"Di Palo","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania \u00abL. Vanvitelli\u00bb, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1570-4994","authenticated-orcid":false,"given":"Mariaceleste","family":"Pezzullo","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania \u00abL. Vanvitelli\u00bb, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Burioni","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Virology, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5421-3552","authenticated-orcid":false,"given":"Aniello","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania \u00abL. Vanvitelli\u00bb, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1822-9861","authenticated-orcid":false,"given":"Nicola","family":"Clementi","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Virology, Vita-Salute San Raffaele University, 20132 Milan, Italy"},{"name":"Laboratory of Microbiology and Virology, IRCCS-San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9736-792X","authenticated-orcid":false,"given":"Nicoletta","family":"Potenza","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania \u00abL. 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