A risk marker of tribasic hemagglutinin cleavage site in influenza A (H9N2) virus

Abstract

Low pathogenic avian influenza A(H9N2) virus is endemic worldwide and continually recruit internal genes to generate human-infecting H5N1, H5N6, H7N9, and H10N8 influenza variants. Here we show that hemagglutinin cleavage sites (HACS) of H9N2 viruses tended to mutate towards hydrophilic via evolutionary transition, and the tribasic HACS were found at high prevalence in Asia and the Middle East. Our finding suggested that the tribasic H9N2 viruses increased the viral replication, stability, pathogenicity and transmission in chickens and the virulence of mice\xa0compared to the monobasic\xa0H9N2 viruses. Notably, the enlarged stem-loop structures of HACS in the RNA region were found in the increasing tribasic H9N2 viruses. The enlarged HACS RNA secondary structures of H9N2 viruses did not influence the viral replication but accelerated the frequency of nucleotide insertion in HACS. With the prevailing tendency of the tribasic H9N2 viruses, the tribasic HACS in H9N2 viruses should be paid more attention. Jiahao Zhang, Kaixiong Ma, and Bo Li et al. identify a variant of the H9N2 avian influenza virus within the hemagglutinin cleavage site required for viral infection. They show that this variant leads to higher viral replication in cells and more virulent disease in both chickens and mice.