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In recent years, human cases infected with the H10N8, H9N2, and H7N9 of avian influenza viruses (AIVs) have been identified frequently as have the internal genes of H7N9 and H10N8, which are derived from H9N2 viruses. The adaptive mutation of the PB2 gene is an important way for the H10N8, H9N2, and H7N9 AIVs to spread across species to adapt to new hosts. Several well\u2010known adaptive mutations in the PB2 gene, such as E627K, D701N, and A588V, significantly enhanced the virulence of the AIVs in mammals. However, the co\u2010adaptation of AIVs to avian and mammalian hosts is rarely studied. In this study, we found that the mutations of PB2\u2010I292V, PB2\u2010R389K, PB2\u2010A588V, PB2\u2010T598M\/V, PB2\u2010L648V, and PB2\u2010T676M substitutions significantly increased after 2012. In addition, in our previous studies, we found that the human\u2010origin and avian\u2010origin of H10N8 AIVs with very high homology also have these six mutation differences in PB2 gene, and the avian\u2010origin H10N8 strain known as JX102 with all the key amino acids on the PB2 protein in the pre\u2010evolutionary stage, so JX102 was chosen as a model strain. Among them, PB2\u2010A588V significantly enhanced the activity of polymerase in avian and mammalian cells. Notably, animal experiments showed that PB2\u2010A588V substitution increased the pathogenicity and transmissibility in chickens and the virulence of mice. The combined mutations of PB2\u2010F6 (including PB2\u2010I292V, PB2\u2010R389K, PB2\u2010A588V, PB2\u2010T598M, PB2\u2010L648V, and PB2\u2010T676M) obtained higher adaptability of AIVs in avians and mammals than that of the single mutation of PB2\u2010A588V, which suggested that the PB2 588 site is a key co\u2010adaptation site and that synergies with other mutation sites can further enhance this co\u2010adaptability. The results of this study show that the emergence of co\u2010adaptation not only increases the threat to avians and mammals but may also contribute to a pandemic among avians and cross the interspecies barrier to mammals.<\/jats:p>","DOI":"10.1111\/tbed.14157","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T03:45:35Z","timestamp":1621395935000},"page":"1794-1803","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The PB2 co\u2010adaptation of H10N8 avian influenza virus increases the pathogenicity to chickens and mice"],"prefix":"10.1155","volume":"69","author":[{"given":"Bo","family":"Li","sequence":"first","affiliation":[{"name":"National Avian Influenza Para\u2010Reference Laboratory, College of Veterinary Medicine South China Agricultural University  Guangzhou China"},{"name":"Guangdong Laboratory for Lingnan Modern Agriculture  Guangzhou China"},{"name":"Key Laboratory of 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China Agricultural University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8780-1497","authenticated-orcid":false,"given":"Jiahao","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Avian Influenza Para\u2010Reference Laboratory, College of Veterinary Medicine South China Agricultural University  Guangzhou China"},{"name":"Guangdong Laboratory for Lingnan Modern Agriculture  Guangzhou China"},{"name":"Key Laboratory of Zoonoses Ministry of Agricultural and Rural Affairs of the People's Republic of China  Guangzhou China"},{"name":"National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control National Development and Reform Commission of the People's Republic of China  Guangzhou China"},{"name":"Key Laboratory of Zoonoses Prevention and Control of Guangdong Province  Guangzhou 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