The PB2 co-adaptation of H10N8 avian influenza virus increases the pathogenicity to chickens and mice.

Avian influenza (AI) is an important zoonotic disease, which can be transmitted across species barriers to other hosts, especially humans, posing a serious threat to the poultry industry and public health. 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-known adaptive mutations in the PB2 gene, such as E627K, D701N, and A588V, significantly enhanced the virulence of the AIVs in mammals. However, the co-adaptation of AIVs to avian and mammalian hosts is rarely studied. In this study, we found that the mutations of PB2-I292V, PB2-R389K, PB2-A588V, PB2-T598M/V, PB2-L648V, and PB2-T676M substitutions significantly increased after 2012. In addition, in our previous studies, we found that the human-origin and avian-origin of H10N8 AIVs with very high homology also have these six mutation differences in PB2 gene, and the avian-origin H10N8 strain known as JX102 with all the key amino acids on the PB2 protein in the pre-evolutionary stage, so JX102 was chosen as a model strain. Among them, PB2-A588V significantly enhanced the activity of polymerase in avian and mammalian cells. Notably, animal experiments showed that PB2-A588V substitution increased the pathogenicity and transmissibility in chickens and the virulence of mice. The combined mutations of PB2-F6 (including PB2-I292V, PB2-R389K, PB2-A588V, PB2-T598M, PB2-L648V, and PB2-T676M) obtained higher adaptability of AIVs in avians and mammals than that of the single mutation of PB2-A588V, which suggested that the PB2 588 site is a key co-adaptation site and that synergies with other mutation sites can further enhance this co-adaptability. The results of this study show that the emergence of co-adaptation 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.

Structure and receptor binding preferences of recombinant hemagglutinins from avian and human H6 and H10 influenza A virus subtypes.

UNLABELLED: During 2013, three new avian influenza A virus subtypes, A(H7N9), A(H6N1), and A(H10N8), resulted in human infections. While the A(H7N9) virus resulted in a significant epidemic in China across 19 provinces and municipalities, both A(H6N1) and A(H10N8) viruses resulted in only a few human infections. This study focuses on the major surface glycoprotein hemagglutinins from both of these novel human viruses. The detailed structural and glycan microarray analyses presented here highlight the idea that both A(H6N1) and A(H10N8) virus hemagglutinins retain a strong avian receptor binding preference and thus currently pose a low risk for sustained human infections. IMPORTANCE: Human infections with zoonotic influenza virus subtypes continue to be a great public health concern. We report detailed structural analysis and glycan microarray data for recombinant hemagglutinins from A(H6N1) and A(H10N8) viruses, isolated from human infections in 2013, and compare them with hemagglutinins of avian origin. This is the first structural report of an H6 hemagglutinin, and our results should further the understanding of these viruses and provide useful information to aid in the continuous surveillance of these zoonotic influenza viruses.