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Most existing antiviral studies of JEV mainly focus on the host factor of the dead-end hosts. However, little research has addressed this in swine. Here, we found that swine interferon alpha-inducible protein 6 (sIFI6) possessed antiviral activity against JEV. <jats:italic>In vitro<\/jats:italic> studies showed that overexpression of sIFI6 inhibited the infection of JEV, while sIFI6 knockdown enhanced the infection of JEV in PK-15 cells. In addition, we also found that the structural integrity of sIFI6 was required by anti-JEV activity and that sIFI6 interacted with JEV nonstructural protein 4A (NS4A), an integral membrane protein with a pivotal function in replication complex during JEV replication. The interaction domain was mapped to the fourth transmembrane domain (TMD), also known as the 2K peptide of NS4A. The antiviral activity of sIFI6 was regulated by endoplasmic reticulum (ER) stress-related protein, Bip. <jats:italic>In vivo<\/jats:italic> studies revealed that sIFI6 alleviated symptoms of JEV infection in C57BL\/6\u2009mice. In addition, the antiviral spectrum of sIFI6 showed that sIFI6 specifically inhibited JEV infection. In conclusion, this study identified sIFI6 as a host factor against JEV infection for the first time. Our findings provide a potential drug target against JEV infection.<\/jats:p>","DOI":"10.1099\/jgv.0.001847","type":"journal-article","created":{"date-parts":[[2023,4,25]],"date-time":"2023-04-25T16:44:10Z","timestamp":1682441050000},"source":"Crossref","is-referenced-by-count":4,"title":["Swine IFI6 confers antiviral effects against Japanese encephalitis virus in vitro and in vivo"],"prefix":"10.1099","volume":"104","author":[{"given":"Liuxing","family":"Qin","sequence":"first","affiliation":[{"name":"Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, PR China"},{"name":"National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenchun","family":"Fan","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, PR 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