Dual E627K and D701N mutations in the PB2 protein of A(H7N9) influenza virus increased its virulence in mammalian models

Zhu, Wenfei; Li, Long; Yan, Zhigang; Gan, Tanhuan; Li, Lifeng; Chen, Rirong; Chen, Ruidong; Zheng, Zongtai; Hong, Wei; Wang, Jia; Smith, David K.; Guan, Yi; Zhu, Han; Shu, Yuelong

doi:10.1038/srep14170

Cited by 55 publications

(50 citation statements)

References 23 publications

(43 reference statements)

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“…Of these four substitutions, PB2-D701N and PA-N359S were shared among GD/3 virus subpopulations from all four inoculated ferrets and from the infected exposed animal. The PB2-D701N mutation facilitates adaptation of avian influenza viruses to mammals (Li et al, 2005) and has been reported to contribute to transmission of H7N9 virus among ferrets (Zhu et al, 2015). However, the PB2-D701N and PA-N359S mutations were not detected in virus populations isolated from ferrets exposed to rGD/3-NA294R or rGD/3-NA294K, indicating that these two mutations are not necessary for HPAI H7N9 respiratory droplet transmissibility in ferrets.…”

Section: Resultsmentioning

confidence: 99%

A Highly Pathogenic Avian H7N9 Influenza Virus Isolated from A Human Is Lethal in Some Ferrets Infected via Respiratory Droplets

Imai

Watanabe

Kiso

et al. 2017

Cell Host & Microbe

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SUMMARY Low pathogenic H7N9 influenza has recently evolved to become highly pathogenic, raising concerns of a pandemic, particularly if these viruses acquire efficient human-to-human transmissibility. We compared a low pathogenic H7N9 virus with a highly pathogenic isolate, and two of its variants that represent neuraminidase inhibitor-sensitive and -resistant subpopulations detected within the isolate. The highly pathogenic H7N9 viruses replicated efficiently in mice, ferrets, and/or nonhuman primates, and were more pathogenic in mice and ferrets than the low pathogenic H7N9 virus, with the exception of the neuraminidase inhibitor-resistant virus, which showed mild-to-moderate attenuation. All viruses transmitted among ferrets via respiratory droplets, and the neuraminidase-sensitive variant killed several of the infected and exposed animals. Neuraminidase inhibitors showed limited effectiveness against these viruses in vivo, but the viruses were susceptible to a polymerase inhibitor. These results suggest that the highly pathogenic H7N9 virus has pandemic potential and should be closely monitored.

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Section: Resultsmentioning

confidence: 99%

A Highly Pathogenic Avian H7N9 Influenza Virus Isolated from A Human Is Lethal in Some Ferrets Infected via Respiratory Droplets

Imai

Watanabe

Kiso

et al. 2017

Cell Host & Microbe

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123

135

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“…During the three waves, a reduced number of human H7N9 viruses retained the residue with 186G or 226Q. The majority of human origin H7N9 viruses of each wave acquired PB2-E627K, which increased viral pathogenicity in mice (17)(18)(19). Of note, almost all of the human-or avian-origin H7N9 viruses possessed the I368V mutation in PB1 protein, which would increase the H5N1 viral transmissibility in ferrets (20).…”

Section: Resultsmentioning

confidence: 99%

Two Outbreak Sources of Influenza A (H7N9) Viruses Have Been Established in China

Wang

Yang

Zhu

et al. 2016

J Virol

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Due to enzootic infections in poultry and persistent human infections in China, influenza A (H7N9) virus has remained a public health threat. The Yangtze River Delta region, which is located in eastern China, is well recognized as the original source for H7N9 outbreaks. Based on the evolutionary analysis of H7N9 viruses from all three outbreak waves since 2013, we identified the Pearl River Delta region as an additional H7N9 outbreak source. H7N9 viruses are repeatedly introduced from these two sources to the other areas, and the persistent circulation of H7N9 viruses occurs in poultry, causing continuous outbreak waves. Poultry movements may contribute to the geographic expansion of the virus. In addition, the AnH1 genotype, which was predominant during wave 1, was replaced by JS537, JS18828, and AnH1887 genotypes during waves 2 and 3. The establishment of a new source and the continuous evolution of the virus hamper the elimination of H7N9 viruses, thus posing a long-term threat of H7N9 infection in humans. Therefore, both surveillance of H7N9 viruses in humans and poultry and supervision of poultry movements should be strengthened. IMPORTANCESince its occurrence in humans in eastern China in spring 2013, the avian H7N9 viruses have been demonstrating the continuing pandemic threat posed by the current influenza ecosystem in China. As the viruses are silently circulated in poultry, with potentially severe outcomes in humans, H7N9 virus activity in humans in China is very important to understand. In this study, we identified a newly emerged H7N9 outbreak source in the Pearl River Delta region. Both sources in the Yangtze River Delta region and the Pearl River Delta region have been established and found to be responsible for the H7N9 outbreaks in mainland China.

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“…HA27, NA28, PB229, PB1-F230, NEP31 and NS32) have been reported to contribute to increased pathogenicity and/or adaptation in human or mammalian hosts. Despite these extensive studies, the molecular determinants for IAV virulence and cross-species adaptation in humans remain incompletely understood33.…”

Section: Discussionmentioning

confidence: 99%

Amino acid substitutions V63I or A37S/I61T/V63I/V100A in the PA N-terminal domain increase the virulence of H7N7 influenza A virus

Chu

Zhang

et al. 2016

Sci Rep

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The PA N-terminal domain (PA-Nter) is essential for viral transcription and replication. Here we identified PA-Nter substitutions A37S, I61T, V63I and V100A in recently emerged avian influenza A viruses (IAVs) with potential effect on virus pathogenicity and/or host adaptation. We introduced the identified PA-Nter substitutions into avian H7N7 IAV by reverse genetics. Our results showed that single substitution V63I and combined substitutions, I61T/V63I and A37S/I61T/V63I/V100A (Mfour), significantly increased virus growth capacity in mammalian cells. Meanwhile, these substitutions conferred higher virus transcription/replication capacity by producing more mRNA, cRNA and vRNA. Consistently, the polymerase activity and the endonuclease activity were enhanced by these PA-Nter substitutions. Notably, substitutions V63I and Mfour strongly increased virus replication and virulence in mice. Collectively, our findings demonstrated that the PA-Nter substitutions V63I and Mfour enhanced IAV pathogenicity through modification of the polymerase activity and the endonuclease activity, which added to the evolving knowledge of IAV virulence determinants.

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Dual E627K and D701N mutations in the PB2 protein of A(H7N9) influenza virus increased its virulence in mammalian models

Cited by 55 publications

References 23 publications

A Highly Pathogenic Avian H7N9 Influenza Virus Isolated from A Human Is Lethal in Some Ferrets Infected via Respiratory Droplets

A Highly Pathogenic Avian H7N9 Influenza Virus Isolated from A Human Is Lethal in Some Ferrets Infected via Respiratory Droplets

Two Outbreak Sources of Influenza A (H7N9) Viruses Have Been Established in China

Amino acid substitutions V63I or A37S/I61T/V63I/V100A in the PA N-terminal domain increase the virulence of H7N7 influenza A virus

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