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However, the development of LAIV is challenging since a proper balance between immunogenicity and safety has to be reached. In this study, we took advantage of reverse genetics to generate three LAIV based on the pandemic H1N1 2009 (pH1N1\/09) virus strain: \u0394PA-X, which is defective in the synthesis of the accessory PA-X protein, NS1(1-126) lacking 93 amino acids at the C-terminus of the NS1 protein, and a combination of both. Characterization of these recombinant viruses using a novel porcine bronchiolar epithelial cell line (T3) revealed that the \u0394PA-X mutant replicated similar to wild type (WT) virus. However, in contrast to the parental virus the \u0394PA-X mutant allowed transcription of genes involved in cell cycle progression and limits apoptosis. The NS1(1-126) mutant also replicated comparable to WT virus, but triggered the release of type I and III IFN and several chemokines and cytokines. Surprisingly, only the NS1(1-126)\/\u0394PA-X double mutant was significantly attenuated on T3 cells, and this was associated with enhanced transcription of genes of the innate immune system and complete absence of apoptosis induction. In conclusion, these findings indicate that NS1 and PA-X act in a concerted manner to manipulate the host cell response, which may help to develop swine LAIV vaccine with a more favorable balance of safety and immunogenicity.<\/jats:p>","DOI":"10.3389\/fcimb.2023.1222805","type":"journal-article","created":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T11:16:57Z","timestamp":1690370217000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["NS1 and PA-X of H1N1\/09 influenza virus act in a concerted manner to manipulate the innate immune response of porcine respiratory epithelial cells"],"prefix":"10.3389","volume":"13","author":[{"given":"Robin","family":"Avanthay","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Obdulio","family":"Garcia-Nicolas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert","family":"Zimmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Summerfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6936","DOI":"10.1038\/s41467-022-34500-5","article-title":"H7N9 avian influenza virus infection in men is associated with testosterone depletion","volume":"13","author":"Bai","year":"2022","journal-title":"Nat. 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