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      Emergence and Adaptation of a Novel Highly Pathogenic H7N9 Influenza Virus in Birds and Humans from a 2013 Human-Infecting Low-Pathogenic Ancestor

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          ABSTRACT

          Since its emergence in 2013, the H7N9 low-pathogenic avian influenza virus (LPAIV) has been circulating in domestic poultry in China, causing five waves of human infections. A novel H7N9 highly pathogenic avian influenza virus (HPAIV) variant possessing multiple basic amino acids at the cleavage site of the hemagglutinin (HA) protein was first reported in two cases of human infection in January 2017. More seriously, those novel H7N9 HPAIV variants have been transmitted and caused outbreaks on poultry farms in eight provinces in China. Herein, we demonstrate the presence of three different amino acid motifs at the cleavage sites of these HPAIV variants which were isolated from chickens and humans and likely evolved from the preexisting LPAIVs. Animal experiments showed that these novel H7N9 HPAIV variants are both highly pathogenic in chickens and lethal to mice. Notably, human-origin viruses were more pathogenic in mice than avian viruses, and the mutations in the PB2 gene associated with adaptation to mammals (E627K, A588V, and D701N) were identified by next-generation sequencing (NGS) and Sanger sequencing of the isolates from infected mice. No polymorphisms in the key amino acid substitutions of PB2 and HA in isolates from infected chicken lungs were detected by NGS. In sum, these results highlight the high degree of pathogenicity and the valid transmissibility of this new H7N9 variant in chickens and the quick adaptation of this new H7N9 variant to mammals, so the risk should be evaluated and more attention should be paid to this variant.

          IMPORTANCE Due to the recent increased numbers of zoonotic infections in poultry and persistent human infections in China, influenza A(H7N9) virus has remained a public health threat. Most of the influenza A(H7N9) viruses reported previously have been of low pathogenicity. Now, these novel H7N9 HPAIV variants have caused human infections in three provinces and outbreaks on poultry farms in eight provinces in China. We analyzed the molecular features and compared the relative characteristics of one H7N9 LPAIV and two H7N9 HPAIVs isolated from chickens and two human-origin H7N9 HPAIVs in chicken and mouse models. We found that all HPAIVs both are highly pathogenic and have valid transmissibility in chickens. Strikingly, the human-origin viruses were more highly pathogenic than the avian-origin viruses in mice, and dynamic mutations were confirmed by NGS and Sanger sequencing. Our findings offer important insight into the origin, adaptation, pathogenicity, and transmissibility of these viruses to both poultry and mammals.

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          Author and article information

          Contributors
          Role: Editor
          Journal
          J Virol
          J. Virol
          jvi
          jvi
          JVI
          Journal of Virology
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0022-538X
          1098-5514
          25 October 2017
          2 January 2018
          15 January 2018
          : 92
          : 2
          : e00921-17
          Affiliations
          [a ]National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
          [b ]Center for Influenza Research and Early-Warning (CASCIRE), Chinese Academy of Sciences, Beijing, China
          [c ]CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
          [d ]Institute of Pathogen Biology, Taishan Medical College, Taian, Shandong, China
          [e ]Key Laboratory of Zoonoses, Key Laboratory of Animal Vaccine Development, Ministry of Agriculture, Guangzhou, China
          [f ]CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
          [g ]Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
          [h ]Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China
          [i ]Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, School of Life and Environmental Sciences, and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia
          [j ]College of Global Change and Earth System Science, Beijing Normal University, Beijing, China
          [k ]Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
          [l ]University of Chinese Academy of Sciences, Beijing, China
          [m ]Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
          St. Jude Children's Research Hospital
          Author notes
          Address correspondence to George F. Gao, gaof@ 123456im.ac.cn , or Ming Liao, mliao@ 123456scau.edu.cn .

          W.Q., W.J., and D.L. contributed equally to this article.

          Citation Qi W, Jia W, Liu D, Li J, Bi Y, Xie S, Li B, Hu T, Du Y, Xing L, Zhang J, Zhang F, Wei X, Eden J-S, Li H, Tian H, Li W, Su G, Lao G, Xu C, Xu B, Liu W, Zhang G, Ren T, Holmes EC, Cui J, Shi W, Gao GF, Liao M. 2018. Emergence and adaptation of a novel highly pathogenic H7N9 influenza virus in birds and humans from a 2013 human-infecting low-pathogenic ancestor. J Virol 92:e00921-17. https://doi.org/10.1128/JVI.00921-17.

          Author information
          http://orcid.org/0000-0001-9596-3552
          http://orcid.org/0000-0001-8176-9951
          http://orcid.org/0000-0002-8717-2942
          Article
          PMC5752946 PMC5752946 5752946 00921-17
          10.1128/JVI.00921-17
          5752946
          29070694
          0e4fe3ba-4fff-4a9b-bfa1-f6e61418fe36
          Copyright © 2018 American Society for Microbiology.

          All Rights Reserved.

          History
          : 6 June 2017
          : 13 September 2017
          Page count
          supplementary-material: 1, Figures: 4, Tables: 1, Equations: 0, References: 30, Pages: 12, Words: 7317
          Funding
          Funded by: National Science Foundation of China;
          Award ID: 31471253
          Award Recipient :
          Funded by: National Key Research and Development Program of China;
          Award ID: 2016YFC1200800
          Award Recipient :
          Funded by: National Natural Science Foundation of China (NSFC), https://doi.org/10.13039/501100001809;
          Award ID: 31672586
          Award Recipient :
          Funded by: National Natural Science Foundation of China (NSFC), https://doi.org/10.13039/501100001809;
          Award ID: U1501212
          Award Recipient :
          Categories
          Genetic Diversity and Evolution
          Custom metadata
          January 2018

          emergence,adaptation,highly pathogenic H7N9 influenza virus,multiple basic amino acids

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