{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:42:38Z","timestamp":1787503358957,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012776","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T00:00:00Z","timestamp":1734566400000}}],"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T00:00:00Z","timestamp":1733702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP233fa627001"],"award-info":[{"award-number":["JP233fa627001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22gm1010009"],"award-info":[{"award-number":["JP22gm1010009"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"JSPS KAKENHI","award":["22H03541"],"award-info":[{"award-number":["22H03541"]}]},{"name":"JST ERATO","award":["JPMJER1902"],"award-info":[{"award-number":["JPMJER1902"]}]},{"DOI":"10.13039\/100016974","name":"Food Science Institute Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100016974","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Since most genetically modified mice are C57BL\/6 background, a mouse-adapted SARS-CoV-2 that causes lethal infection in young C57BL\/6 mice is useful for studying innate immune protection against SARS-CoV-2 infection. Here, we established two mouse-adapted SARS-CoV-2, ancestral and Delta variants, by serial passaging 80 times in C57BL\/6 mice. Although young C57BL\/6 mice were resistant to infection with the mouse-adapted ancestral SARS-CoV-2, the mouse-adapted SARS-CoV-2 Delta variant caused lethal infection in young C57BL\/6 mice. In contrast, MyD88 and IFNAR1 KO mice exhibited resistance to lethal infection with the mouse-adapted SARS-CoV-2 Delta variant. Treatment with recombinant IFN-\u03b1\/\u03b2 at the time of infection protected mice from lethal infection with the mouse-adapted SARS-CoV-2 Delta variant, but intranasal administration of recombinant IFN-\u03b1\/\u03b2 at 2 days post infection exacerbated the disease severity following the mouse-adapted ancestral SARS-CoV-2 infection. Moreover, we showed that TNF-\u03b1 amplified by type I IFN signals exacerbated the SARS-CoV-2 infection by stimulating CXCL1 production from macrophages and neutrophil recruitment into the lung tissue. Finally, we showed that intravenous administration to mice or hamsters with TNF protease inhibitor 2 alleviated the severity of SARS-CoV-2 and influenza virus infection. Our results uncover an unexpected mechanism by which type I interferon-mediated TNF-\u03b1 signaling exacerbates the disease severity and will aid in the development of novel therapeutic strategies to treat respiratory virus infection and associated diseases such as influenza and COVID-19.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012776","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T13:40:35Z","timestamp":1733751635000},"page":"e1012776","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["TNF-\u03b1 exacerbates SARS-CoV-2 infection by stimulating CXCL1 production from 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