Prevailing I292V PB2 mutation in avian influenza H9N2 virus increases viral polymerase function and attenuates IFN-β induction in human cells

Gao, Weihua; Zu, Zhipeng; Liu, Jiyu; Song, Jingwei; Wang, Xinyu; Wang, Chenxi; Liu, Litao; Qi, Ting; Wang, Mingyang; Sun, Honglei; Sun, Yipeng; Liu, Jinhua; Chang, Kin-Chow; Pu, Juan

doi:10.1099/jgv.0.001294

Cited by 36 publications

(31 citation statements)

References 34 publications

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“…Several residues in the PB2 protein have been previously identified as virulence markers as well as factors contributing to interspecies transmission of influenza A viruses in mammals (39,(46)(47)(48)(49). In particular, some mutations, such as E627K, D701N, E158R, A271T, Q591R, H357N, T558I, K339T, A588T, I147T, and I292V (46,47,(50)(51)(52)(53)(54)(55)(56), in the PB2 protein are essential to determine the pathogenesis of influenza viruses in mammals. In this study, we first demonstrated that the PB2 protein had a major effect on the viral pathogenicity of two H1N1 SIVs, with the other genes playing only minor roles in virulence.…”

Section: Discussionmentioning

confidence: 99%

A Single Amino Acid at Position 431 of the PB2 Protein Determines the Virulence of H1N1 Swine Influenza Viruses in Mice

et al. 2020

J Virol

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The frequent reassortment among different influenza viruses in pigs adds complexity to the epidemiology of swine influenza. The diverse viral virulence phenotypes underline the need to investigate the possible genetic determinants for evaluating the pandemic potential to human public health. Here, we found that multiple genotypes of influenza viruses cocirculate in the swine population in Liaoning Province, China. Furthermore, we pinpointed a single amino acid at position 431 in the PB2 protein which plays a critical role in the virulence of H1N1 viruses in mice and found that the alteration of viral polymerase activities is the cause of the different virulence. Our study further indicated that the virulence of influenza virus is a polygenic trait, and the newly identified virulence-related residue in the PB2 provides important information for broadening knowledge on the genetic basis of viral virulence of influenza viruses.

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Section: Discussionmentioning

confidence: 99%

A Single Amino Acid at Position 431 of the PB2 Protein Determines the Virulence of H1N1 Swine Influenza Viruses in Mice

et al. 2020

J Virol

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“…We have listed and analyzed the potential virulence determinants in the HA, NA, PB2 and NS1 genes of the two viruses in Table S3. Among these mutations, I292V and A588V in PB2 genes have been reported associated with increased polymerase activity in mammalian and/or avian cell line and increased virulence in mice [49,50]. The two mutations were observed in GS38 virus but not DK09 virus, which might contribute to the difference of the mean death time.…”

Section: Discussionmentioning

confidence: 97%

Host Innate Immune Response of Geese Infected with Clade 2.3.4.4 H5N6 Highly Pathogenic Avian Influenza Viruses

Huang

et al. 2020

Microorganisms

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Since 2014, highly pathogenic avian influenza (HPAI) H5N6 viruses have circulated in waterfowls and caused human infections in China, posing significant threats to the poultry industry and the public health. However, the genetics, pathogenicity and innate immune response of H5N6 HPAIVs in geese remain largely unknown. In this study, we analyzed the genetic characteristic of the two H5N6 viruses (GS38 and DK09) isolated from apparently healthy domestic goose and duck in live poultry markets (LPMs) of Southern China in 2016. Phylogenetic analysis showed that the HA genes of the two H5N6 viruses belonged to clade 2.3.4.4 and were clustered into the MIX-like group. The MIX-like group viruses have circulated in regions such as China, Japan, Korea, and Vietnam. The NA genes of the two H5N6 viruses were classified into the Eurasian sublineage. The internal genes including PB2, PB1, PA, NP, M, and NS of the two H5N6 viruses derived from the MIX-like. Therefore, our results suggested that the two H5N6 viruses were reassortants of the H5N1 and H6N6 viruses and likely derived from the same ancestor. Additionally, we evaluated the pathogenicity and transmission of the two H5N6 viruses in domestic geese. Results showed that both the two viruses caused serious clinical symptoms in all inoculated geese and led to high mortality in these birds. Both the two viruses were transmitted efficiently to contact geese and caused lethal infection in these birds. Furthermore, we found that mRNA of pattern recognition receptors (PRRs), interferons (IFNs), and stimulated genes (ISGs) exhibited different levels of activation in the lungs and spleens of the two H5N6 viruses-inoculated geese though did not protect these birds from H5N6 HPAIVs infection. Our results suggested that the clade 2.3.4.4 waterfowl-origin H5N6 HPAIVs isolated from LPMs of Southern China could cause high mortality in geese and innate immune-related genes were involved in the geese innate immune response to H5N6 HPAIVs infection. Therefore, we should pay more attention to the evolution, pathogenic variations of these viruses and enhance virological surveillance of clade 2.3.4.4 H5N6 HPAIVs in waterfowls in China.

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“…An obvious shortcoming here is that we did not measure IFN-β expression in different cell cultures after the infection with different H5N8/H9N2 reassortants to elucidate the role of PB2 and PA in the inhibition of IFN-response ( Hayashi, MacDonald, and Takimoto 2015a ; Gao et al. 2019 ) or to quantify IFN-β levels in different cells ( Hsu et al.…”

Section: Discussionmentioning

confidence: 99%

“…2010 ; Zhao et al. 2014 ; Hayashi, MacDonald, and Takimoto 2015a ; Gao et al. 2019 ), and synergism with NS1 is required for efficient virus replication in vivo and in vitro ( Varga et al.…”

Section: Discussionmentioning

confidence: 99%

Genetic incompatibilities and reduced transmission in chickens may limit the evolution of reassortants between H9N2 and panzootic H5N8 clade 2.3.4.4 avian influenza virus showing high virulence for mammals

Mostafa

Blaurock²,

Scheibner³

et al. 2020

Virus Evolution

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The unprecedented spread of H5N8- and H9N2-subtype avian influenza virus (AIV) in birds across Asia, Europe, Africa and North America poses a serious public health threat with a permanent risk of reassortment and the possible emergence of novel virus variants with high virulence in mammals. To gain information on this risk we studied the potential for reassortment between two contemporary H9N2 and H5N8 viruses. While the replacement of the PB2, PA and NS genes of highly pathogenic H5N8 by homologous segments from H9N2 produced infectious H5N8 progeny, PB1 and NP of H9N2 were not able to replace the respective segments from H5N8 due to residues outside the packaging region. Furthermore, exchange of the PB2, PA and NS segments of H5N8 by those of H9N2 increased replication, polymerase activity and interferon antagonism of the H5N8 reassortants in human cells. Notably, H5N8 reassortants carrying the H9N2-subtype PB2 segment and to lesser extent the PA or NS segments showed remarkably increased virulence in mice as indicated by rapid onset of mortality, reduced mean time to death and increased body weight loss. Simultaneously, we observed that in chickens the H5N8 reassortants, particularly with the H9N2 NS segment, demonstrated significantly reduced transmission to co-housed chickens. Together, while the limited capacity for reassortment between co-circulating H9N2 and H5N8 viruses and the reduced bird-to-bird transmission of possible H5N8 reassortants in chickens may limit the evolution of such reassortant viruses, they show a higher replication potential in human cells and increased virulence in mammals.

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Prevailing I292V PB2 mutation in avian influenza H9N2 virus increases viral polymerase function and attenuates IFN-β induction in human cells

Cited by 36 publications

References 34 publications

A Single Amino Acid at Position 431 of the PB2 Protein Determines the Virulence of H1N1 Swine Influenza Viruses in Mice

A Single Amino Acid at Position 431 of the PB2 Protein Determines the Virulence of H1N1 Swine Influenza Viruses in Mice

Host Innate Immune Response of Geese Infected with Clade 2.3.4.4 H5N6 Highly Pathogenic Avian Influenza Viruses

Genetic incompatibilities and reduced transmission in chickens may limit the evolution of reassortants between H9N2 and panzootic H5N8 clade 2.3.4.4 avian influenza virus showing high virulence for mammals

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