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Surveillance is important for influenza pandemic preparedness, but the susceptibility of zoonotic IAVs to the cap-dependent endonuclease inhibitor baloxavir acid (BXA) has not been thoroughly researched. Although an amino acid substitution at position 38 in the polymerase acidic protein (PA\/I38) in seasonal IAVs reduces BXA susceptibility, PA polymorphisms at position 38 are rarely seen in zoonotic IAVs. Here, we examined the impact of PA\/I38 substitutions on the BXA susceptibility of recombinant A(H5N1) viruses. PA mutants that harbored I38T, F, and M were 48.2-, 24.0-, and 15.5-fold less susceptible, respectively, to BXA than wild-type A(H5N1) but were susceptible to the neuraminidase inhibitor oseltamivir acid and the RNA polymerase inhibitor favipiravir. PA mutants exhibited significantly impaired replicative fitness in Madin-Darby canine kidney cells at 24 h postinfection. In addition, in order to investigate new genetic markers for BXA susceptibility, we screened geographically and temporally distinct IAVs isolated worldwide from birds and pigs. The results showed that BXA exhibited antiviral activity against avian and swine viruses with similar levels to seasonal isolates. All viruses tested in the study lacked the PA\/I38 substitution and were susceptible to BXA. Isolates harboring amino acid polymorphisms at positions 20, 24, and 37, which have been implicated in the binding of BXA to the PA endonuclease domain, were also susceptible to BXA. These results suggest that monitoring of the PA\/I38 substitution in animal-derived influenza viruses is important for preparedness against zoonotic influenza virus outbreaks.<\/jats:p>","DOI":"10.1007\/s00705-023-05958-5","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T17:02:33Z","timestamp":1705078953000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The impact of PA\/I38 substitutions and PA polymorphisms on the susceptibility of zoonotic influenza A viruses to baloxavir"],"prefix":"10.1007","volume":"169","author":[{"given":"Keiichi","family":"Taniguchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Noshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Omoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2549-0945","authenticated-orcid":false,"given":"Takao","family":"Shishido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Matsuno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatoshi","family":"Okamatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Krauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J","family":"Webby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Sakoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Kida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,12]]},"reference":[{"key":"5958_CR1","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/S0140-6736(17)30129-0","volume":"390","author":"C Paules","year":"2017","unstructured":"Paules C, Subbarao K (2017) Influenza. 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Euro Surveill 24:","DOI":"10.2807\/1560-7917.ES.2019.24.3.1800698"},{"key":"5958_CR51","doi-asserted-by":"publisher","unstructured":"Jones JC, Kumar G, Barman S et al (2018) Identification of the I38T PA substitution as a resistance marker for next-generation influenza virus endonuclease inhibitors. mBio 9(2). https:\/\/doi.org\/10.1128\/mBio.00430-18","DOI":"10.1128\/mBio.00430-18"}],"container-title":["Archives of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00705-023-05958-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00705-023-05958-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00705-023-05958-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T04:31:19Z","timestamp":1707453079000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00705-023-05958-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,12]]},"references-count":51,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,2]]}},"alternative-id":["5958"],"URL":"https:\/\/doi.org\/10.1007\/s00705-023-05958-5","relation":{},"ISSN":["0304-8608","1432-8798"],"issn-type":[{"value":"0304-8608","type":"print"},{"value":"1432-8798","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,12]]},"assertion":[{"value":"23 August 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 November 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 January 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All experiments were authorized by the Biosafety Management Committee on Pathogens and Other Hazardous Agents and the Safety Committee on Genetic Recombination Experiments, Hokkaido University. Regarding dual-use experiments, we have described the experiment plan, the progress of the experiment, and its safety assurance, and we have received approval for the contents from this committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}},{"value":"K.T., T.N., S.O., A.S., T.S., and A.N. are employees of Shionogi & Co., Ltd. K.M., M.O., Y.S., and H.K. received financial support from Shionogi & Co., Ltd. for the studies reported in this article. Shionogi & Co., Ltd. financially supported all work related to this study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}}],"article-number":"29"}}