Amino Acid 316 of Hemagglutinin and the Neuraminidase Stalk Length Influence Virulence of H9N2 Influenza Virus in Chickens and Mice

Sun, Yipeng; Tan, Yuanyuan; Wei, Kai; Sun, Honglei; Shi, Yi; Pu, Juan; Yang, Hanchun; Gao, George F.; Yin, Ye; Feng, Wen-hai; Pérez, Daniel R.; Liu, Jinhua

doi:10.1128/jvi.02688-12

Cited by 73 publications

(84 citation statements)

References 30 publications

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“…In the quail study, we also found that the molecular changes due to mammalian adaptation did not affect the ability of the virus to replicate when both ferret-adapted surface genes were present. It has been reported that a functional balance between HA and NA activity is important for virus replication and transmission (Sun et al, 2013;Yen et al, 2011). An imbalance caused by an avian-origin HA and a mammalian-origin NA may account for the lack of proper replication and transmission…”

Section: Discussionmentioning

confidence: 99%

Replication and transmission of mammalian-adapted H9 subtype influenza virus in pigs and quail

Obadan

Kimble

Rajão

et al. 2015

Journal of General Virology

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Influenza A virus is a major pathogen of birds, swine and humans. Strains can jump between species in a process often requiring mutations and reassortment, resulting in outbreaks and, potentially, pandemics. H9N2 avian influenza is predominant in poultry across Asia and occasionally infects humans and swine. Pandemic H1N1 (H1N1pdm) is endemic in humans and swine and has a history of reassortment in pigs. Previous studies have shown the compatibility of H9N2 and H1N1pdm for reassortment in ferrets, a model for human infection and transmission. Here, the effects of ferret adaptation of H9 surface gene segments on the infectivity and transmission in at-risk natural hosts, specifically swine and quail, were analysed. Reassortant H9N1 and H9N2 viruses, carrying seven or six gene segments from H1N1pdm, showed infectivity and transmissibility in swine, unlike the wholly avian H9N2 virus with ferretadapted surface genes. In quail, only the reassortant H9N2 with the six internal gene segments from the H1N1pdm strain was able to infect and transmit, although less efficiently than the wholly avian H9N2 virus with ferret-adapted surface genes. These results highlight that ferretadapted mutations on the haemagglutinin of H9 subtype virus do not restrict the ability of the virus to infect swine and quail, and that the ability to transmit in these species depends on the context of the whole virus. As such, this study emphasizes the threat that H9N2 reassortant viruses pose to humans and agricultural species and the importance of the genetic constellation of the virus to its ability to replicate and transmit in natural hosts of influenza.

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Section: Discussionmentioning

confidence: 99%

Replication and transmission of mammalian-adapted H9 subtype influenza virus in pigs and quail

Obadan

Kimble

Rajão

et al. 2015

Journal of General Virology

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“…Some mutations, however, are found to confer improved infection of both birds and mammals. For example, our previous study revealed that H9N2 viruses with an HA-A316S substitution and/or a shorter neuraminidase (NA) stalk are predominantly prevalent in avian strains and can increase virulence in chickens and mice (44). Thus, emerging or even established mutations in avian strains can exhibit increased viral infectivity in mammalian host species, which in turn could be different in avian species.…”

Section: Figmentioning

confidence: 99%

Prevailing PA Mutation K356R in Avian Influenza H9N2 Virus Increases Mammalian Replication and Pathogenicity

Zhang

Gao

et al. 2016

J Virol

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Adaptation of the viral polymerase complex comprising PB1, PB2, and PA is necessary for efficient influenza A virus replication in new host species. We found that PA mutation K356R (PA-K356R) has become predominant since 2014 in avian H9N2 viruses in China as with seasonal human H1N1 viruses. The same mutation is also found in most human isolates of emergent avian H7N9 and H10N8 viruses whose six internal gene segments are derived from the H9N2 virus. We further demonstrated the mammalian adaptive functionality of the PA-K356R mutation. Avian H9N2 virus with the PA-K356R mutation in human A549 cells showed increased nuclear accumulation of PA and increased viral polymerase activity that resulted in elevated levels of viral transcription and virus output. The same mutant virus in mice also enhanced virus replication and caused lethal infection. In addition, combined mutation of PA-K356R and PB2-E627K, a well-known mammalian adaptive marker, in the H9N2 virus showed further cooperative increases in virus production and severity of infection in vitro and in vivo. In summary, PA-K356R behaves as a novel mammalian tropism mutation, which, along with other mutations such as PB2-E627K, might render avian H9N2 viruses adapted for human infection. IMPORTANCE Mutations of the polymerase complex (PB1, PB2, and PA) of influenza A virus are necessary for viral adaptation to new hosts.This study reports a novel and predominant mammalian adaptive mutation, PA-K356R, in avian H9N2 viruses and human isolates of emergent H7N9 and H10N8 viruses. We found that PA-356R in H9N2 viruses causes significant increases in virus replication and severity of infection in human cells and mice and that PA-K356R cooperates with the PB2-E627K mutation, a wellcharacterized human adaptive marker, to exacerbate mammalian infection in vitro and in vivo. Therefore, the PA-K356R mutation is a significant adaptation in H9N2 viruses and related H7N9 and H10N8 reassortants toward human infectivity. The emergence of new pandemic influenza A viruses requires overcoming barriers to cross-species transmission from animal reservoirs to human populations. Influenza viruses of the H9N2 subtype and their reassortants circulating in poultry are a potential source of pandemic viruses and hence represent a significant public health threat (1). Since spring 2013, a novel avian H7N9 reassortant with six internal genes of the H9N2 virus had caused three major outbreaks in humans throughout China (2, 3). During the same period, a newly emergent avian H10N8 virus, also with six H9N2-like internal genes, was reported to cause fatal human infections in China (4). In the meantime, H9N2 viruses continued to cause human infections in China and other countries based on etiological and serological evidence (5-12). We recently found that avian H9N2 viruses have undergone significant genetic evolution, especially in their internal genes, to form a predominant genotype (G57), which in turn provided the internal genes to multiple new subtypes, including H7N9 and H10N8 viru...

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“…Two other substitutions (N313D and N496S) in the HA of an H9N2 AIV have been shown to enhance binding to both ␣2,3-linked sialic acid (SA␣2,3) and SA␣2,6 receptors (27). Some amino acid mutations such as A316S in HA and M147L, D253N, A588V, Q591K, E627K, and D701N in PB2 have been identified to play a critical role in enhancing replication of AIVs in mammals (23,(28)(29)(30)(31).…”

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confidence: 99%

A Single Mutation at Position 190 in Hemagglutinin Enhances Binding Affinity for Human Type Sialic Acid Receptor and Replication of H9N2 Avian Influenza Virus in Mice

Teng

Shen

et al. 2016

J Virol

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H9N2 avian influenza virus (AIV) has an extended host range, but the molecular basis underlying H9N2 AIV transmission to mammals remains unclear. We isolated more than 900 H9N2 AIVs in our 3-year surveillance in live bird markets in China from 2009 to 2012. Thirty-seven representative isolates were selected for further detailed characterization. These isolates were categorized into 8 genotypes (B64 to B71) and formed a distinct antigenic subgroup. Three isolates belonging to genotype B69, which is a predominant genotype circulating in China, replicated efficiently in mice, while the viruses tested in parallel in other genotypes replicated poorly, although they, like the three B69 isolates, have a leucine at position 226 in the hemagglutinin (HA) receptor binding site, which is critical for binding human type sialic acid receptors. Further molecular and single mutation analysis revealed that a valine (V) residue at position 190 in HA is responsible for efficient replication of these H9N2 viruses in mice. The 190V in HA does not affect virus receptor binding specificity but enhances binding affinity to human cells and lung tissues from mouse and humans. All these data indicate that the 190V in HA is one of the important determinants for H9N2 AIVs to cross the species barrier to infect mammals despite multiple genes conferring adaptation and replication of H9N2 viruses in mammals. Our findings provide novel insights on understanding host range expansion of H9N2 AIVs. IMPORTANCE Influenza virus hemagglutinin (HA) is responsible for binding to host cell receptors and therefore influences the viral host rangeand pathogenicity in different species. We showed that the H9N2 avian influenza viruses harboring 190V in the HA exhibit enhanced virus replication in mice. Further studies demonstrate that 190V in the HA does not change virus receptor binding specificity but enhances virus binding affinity of the H9N2 virus to human cells and attachment to lung tissues from humans and mouse. Our findings suggest that more attention should be given to the H9N2 AIVs with HA-190V during surveillance due to their potential threat to mammals, including humans. Since the first isolate of an avian influenza virus (AIV) H9N2 subtype was reported in the United States in 1966, three distinct lineages of H9N2 viruses that caused outbreaks in domestic poultry in Asia have been identified (1, 2). H9N2 is a predominant subtype of AIVs circulating in poultry farms in Asia and the Middle East and has caused substantial economic losses over the past decade (3-9). Although a large amount of H9N2 vaccines, including inactivated and vectored vaccines, have been used in areas of endemicity, outbreaks caused by H9N2 AIVs are still not efficiently controlled. Importantly, H9N2 AIV has been reported to infect mammals, including humans, pigs, and dogs (10-13), indicating that it has an extended host range. It should be noted that several human infections with an H9N2 AIV have been recorded (14,15). Numerous human infections have also been confirm...

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Amino Acid 316 of Hemagglutinin and the Neuraminidase Stalk Length Influence Virulence of H9N2 Influenza Virus in Chickens and Mice

Cited by 73 publications

References 30 publications

Replication and transmission of mammalian-adapted H9 subtype influenza virus in pigs and quail

Replication and transmission of mammalian-adapted H9 subtype influenza virus in pigs and quail

Prevailing PA Mutation K356R in Avian Influenza H9N2 Virus Increases Mammalian Replication and Pathogenicity

A Single Mutation at Position 190 in Hemagglutinin Enhances Binding Affinity for Human Type Sialic Acid Receptor and Replication of H9N2 Avian Influenza Virus in Mice

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