Evolution of the H9N2 influenza genotype that facilitated the genesis of the novel H7N9 virus

Pu, Juan; Wang, Shuoguo; Yin, Ye; Zhang, Guozhong; Carter, Robert A.; Wang, Jinliang; Xu, Guanlong; Sun, Honglei; Wang, Min; Chu, Wen; Wei, Yandi; Wang, Dongdong; Zhu, Baoli; Lemmon, Gordon; Jiao, Yuannian; Duan, Susu; Wang, Qian; Du, Qian; Sun, Meng; Bao, Jinnan; Sun, Yipeng; Zhao, Jinbiao; Zhang, Hui; Wu, Gang; Liu, Jinhua; Webster, Robert G.

doi:10.1073/pnas.1422456112

Cited by 297 publications

(365 citation statements)

References 34 publications

(71 reference statements)

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“…Our surveillance in LBMs in China during 2009 to 2012 shows that the H9N2 virus was prevalent in chickens; this result is consistent with the finding in a former report that was conducted in farm chickens in China (47). All these results indicate that the H9N2 virus is becoming a predominant virus circulating in domestic poultry in China.…”

Section: Ha-190v Increases Virus Binding To A549 Cellssupporting

confidence: 91%

“…All these results indicate that the H9N2 virus is becoming a predominant virus circulating in domestic poultry in China. Noticeably, the recently identified H9N2 viruses are distinct from the vaccine strains used, indicating that the virus changes very fast, especially the HA gene due to the immunity and selection pressure (47). Rapid antigenic drift and aerosol transmission among birds have been major issues in the attempts to control the H9N2 avian influenza and could accelerate the spread and evolution of H9N2 AIVs (48).…”

Section: Ha-190v Increases Virus Binding To A549 Cellsmentioning

confidence: 99%

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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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Section: Ha-190v Increases Virus Binding To A549 Cellssupporting

confidence: 91%

Section: Ha-190v Increases Virus Binding To A549 Cellsmentioning

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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“…In the meantime, H9N2 viruses continued to cause human infections in China and other countries based on etiological and serological evidence (5)(6)(7)(8)(9)(10)(11)(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 viruses (13). Thus, the evolving internal genes of H9N2 viruses may be a primary genetic source for emergent H9N2 viruses and their reassortants that can confer human infection.…”

mentioning

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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“…The reported case numbers are still increasing [3]. Evidence supports the origination hypothesis of triple reassortment between H9N2 virus and H7 and N9 viruses [4][5][6][7].…”

Section: Introductionmentioning

confidence: 56%

“…This implies that we might be able to predict epidemics caused by H7N9 virus by monitoring the prevalence and variation of H9 virus cOR, Crude odds ratio; aOR, adjusted odds ratio; CI, confidence interval. [5]. Moreover, the risk of H7N9 virus prevalence could also be decreased by reducing the amount of H9 virus in the environment.…”

Section: Discussionmentioning

confidence: 99%

Quantitative risk analysis of the novel H7N9 virus in environments associated with H9 avian influenza virus, Zhejiang province, China

Lin

Wang

et al. 2016

Epidemiol. Infect.

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SUMMARYH9 avian influenza virus played a key role during generation of the novel H7N9 virus. A surveillance programme was conducted to assess the H9 virus in relation to the risk of H7N9 virus contamination in the environment. Risk of H7N9 virus contamination in the presence of H9 virus was higher than without (adjusted odds ratio 4·49, 95% confidence interval 3·79-5·31). Adjusted odds ratios of the H7N9 virus associated with co-presence of H9 virus and interacting factors were 4·93 (rural vs. urban area), 46·80 (live poultry markets vs. other premises), 6·86 (Huzhou vs. Hangzhou prefecture), 40·67 (year 2015 vs. 2013), and 9·63 (sewage from cleaning poultry vs. poultry faeces). Regular surveillance on gene variability of H7N9 and H9 viruses should be conducted and extra measures are needed to reduce co-circulation of H7N9 and H9 viruses in the environment.

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Evolution of the H9N2 influenza genotype that facilitated the genesis of the novel H7N9 virus

Cited by 297 publications

References 34 publications

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

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

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

Quantitative risk analysis of the novel H7N9 virus in environments associated with H9 avian influenza virus, Zhejiang province, China

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