Receptor Binding Properties Of H10 And H9 Influenza Viruses

Influenza virus is a negative sense, single-stranded, segmented RNA virus of the Orthomyxoviridae family. Influenza viruses can be classified into four types (A/B/C/D) on the basis of the antigenic properties of nucleoprotein and matrix protein. Influenza A virus is a zoonotic pathogen that can infect a broad range of species, including birds, pigs, horses and humans.The H1, H2 and H3 subtypes of influenza A viruses have naturally adapted to humans, causing worldwide pandemics and epidemics. In addition, influenza viruses of the H5, H6, H7, H9 and H10 subtypes also have crossed the species barrier and infected humans, posing a threat to human health.Influenza A virus initially binds to SA-linked host cell-surface receptors via the HA and transcribes and replicates following entry into the cell by endocytosis. The a2,6-linked SA receptor is predominantly found in the upper respiratory tract (URT) in humans, and a2,3-linked SA receptors are expressed in the lower respiratory tract (LRT). Thus avian influenza viruses that prefer to bind a2, 3-linked SA receptors are difficult to transmit among humans. However, these viruses can also acquire the ability of human transmission through changing receptor-binding preference by specific amino acid mutations in HA. In this study, we analysed the receptor binding preference of H9 and H10 subtype influenza viruses and explored the mechanism of HA binding to SA receptors of these viruses at atomic level.Since December 2013, at least three cases of human infections with H10N8 avian influenza virus have been reported in China, two of them being fatal. To investigate the epidemic potential of H10N8 viruses, we examined the receptor binding property of the first human isolate A/Jiangxi-Donghu/346/2013 (JD-H10N8), and determined the structures of its haemagglutinin (HA) in complex with both avian and human receptor analogues. Our results demonstrated that JD-H10N8 preferentially binds the avian receptor. Unlike the prevalent H7N9 virus isolate AH-H7N9, JD-H10N8 did not show strong binging affinity to the human receptors. We conclude that the H10N8 virus is a typical avian influenza virus. Its hemagglutinin retains a weak preference for human receptors, which suggests that the current human H10N8 is poorly adapted for efficient human-to-human transmission. Mutant study revealed that Q226L or Q226LG228S increased the binding affinity of JD-H10N8 HA to the human receptor analogue. And according to G1SAID database, two H10N7 subtype influenza viruses islotated from Germany and Denmark (D14 H10) acquire HA226L, and SPR results showed that D14 H10 HA exhibited dual receptor binding ability. Upon mutation or reassortment, this kind of viruses could adapt to the new human host and may start a pandemic, just likeAH-H7N9.Since the first isolation was reported in turkeys in the United States in 1966, the H9N2 avian influenza virus has been circulating widely in the world, posing great threat to poultry farming. It has also been reported to sporadically infect humans since 1990s. In this study, we analyzed the receptor binding abilities of H9N2 viruses systematically, and divided the cource of there evolution into three stages. Initially the H9 HA prefered avian receptor binding; then it acquired human receptor binding ability; and finally H9 HA prefered human receptor binding. We also found the position 158 could confer H9N2 influenza virus to acquire the ability to bind to human receptor and 226L played an important role in switching the receptor binding preference, similar to H2/H3 HA.These findings have led to the concern that H9N2 virus may have the potential to cause a pandemic by mutating or reassorting with human influenza viruses.