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During SARS-CoV-2 infection, however, the immune system often fails to elicit appropriate responses, resulting in cytokine-release syndrome in patients with COVID-19. In this study, we show that reduced expression of Regnase-1, an RNase that negatively regulates immune cell activation, confers resistance to infection with the mouse-adapted SARS-CoV-2 MA10 strain. In\n                    <jats:italic>Regnase-1<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    <jats:sup>\/\u2013<\/jats:sup>\n                    mice, altered neutrophil function contributed to the amelioration of MA10-induced pneumonia. Single-cell RNA sequencing of lung tissue during MA10 infection revealed four distinct neutrophil subsets, and among these, a subset characterized by an interferon-stimulated gene (ISG) signature was decreased in\n                    <jats:italic>Regnase-1<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    <jats:sup>\/\u2013<\/jats:sup>\n                    mice. Furthermore,\n                    <jats:italic>Regnase-1<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    <jats:sup>\/\u2013<\/jats:sup>\n                    neutrophils exhibited reduced ISG expression without corresponding changes in proinflammatory gene expression. Regnase-1 was found to repress the expression of\n                    <jats:italic>Tsc22d3<\/jats:italic>\n                    , a gene involved in the negative regulation of interferon responses, through its 3\u2032 untranslated region. Collectively, these findings suggest that Regnase-1 attenuates resistance to SARS-CoV-2 MA10 infection by promoting excessive interferon responses in neutrophils.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013969","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T18:46:11Z","timestamp":1770662771000},"page":"e1013969","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Regnase-1-mediated regulation of neutrophils modulates SARS-CoV-2 pneumonia"],"prefix":"10.1371","volume":"22","author":[{"given":"Keiko","family":"Yasuda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Aoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shintaro","family":"Shichinohe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chikako","family":"Ono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Vandenbon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiya","family":"Ohara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Muramoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songling","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Motooka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitomi","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiji","family":"Hirota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gen","family":"Kondoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Noda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daron 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