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PB1-F2 is an IAV protein expressed from the second open reading frame of PB1 gene. Small as it is, PB1-F2 is a critical virulence factor. Multiple key amino acid residues and motifs of PB1-F2 have been shown to influence the virulence of IAV in a strain- and host-specific manner, plausibly through the induction of apoptotic cell death, modulation of type I IFN response, activation of inflammasome, and facilitation of secondary bacterial infection. However, the exact role of PB1-F2 in IAV pathogenesis remains unexplained. Through reanalysis of the current literature, we redefine PB1-F2 as an ambivalent innate immune modulator that determines IAV infection outcome through induction of immune cell death, differential modulation of early- and late-type I IFN response, and promotion of pathogenic inflammation. PB1-F2 functions both intracellularly and extracellularly. Further investigations of the mechanistic details of PB1-F2 action will shed new light on immunopathogenesis of IAV infection.<\/jats:p>","DOI":"10.1002\/jlb.4mr0320-206r","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T09:56:10Z","timestamp":1587635770000},"page":"763-771","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Influenza A virus PB1-F2 protein: An ambivalent innate immune modulator and virulence factor"],"prefix":"10.1093","volume":"107","author":[{"given":"Pak-Hin Hinson","family":"Cheung","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, The University of Hong Kong , Pokfulam, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tak-Wang Terence","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The University of Hong Kong , Pokfulam, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Ping","family":"Chan","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The University of Hong Kong , Pokfulam, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2778-3530","authenticated-orcid":false,"given":"Dong-Yan","family":"Jin","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The University of Hong Kong , Pokfulam, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,23]]},"reference":[{"issue":"Suppl 4","key":"2023012312520104300_jlb10622-bib-0001","doi-asserted-by":"crossref","first-page":"D49","DOI":"10.1016\/j.vaccine.2008.07.039","article-title":"The biology of influenza 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