Amino acid substitutions involved in the adaptation of a novel highly pathogenic H5N2 avian influenza virus in mice
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Amino acid substitutions involved in the adaptation of a novel highly pathogenic H5N2 avian influenza virus in mice Haibo Wu, Xiuming Peng, Xiaorong Peng and Nanping Wu*
Abstract Background: H5N2 avian influenza viruses (AIVs) can infect individuals that are in frequent contact with infected birds. In 2013, we isolated a novel reassortant highly pathogenic H5N2 AIV strain [A/duck/Zhejiang/6DK19/2013(H5N2) (6DK19)] from a duck in Eastern China. This study was undertaken to understand the adaptive processes that led enhanced replication and increased virulence of 6DK19 in mammals. 6DK19 was adapted to mice using serial lung-to-lung passages (10 passages total). The virulence of the wild-type virus (WT-6DK19) and mouse-adapted virus (MA-6DK19) was determined in mice. The whole-genome sequences of MA-6DK19 and WT-6DK19 were compared to determine amino acid differences. Findings: Amino acid changes were identified in the MA-DK19 PB2 (E627K), PB1 (I181T), HA (A150S), NS1 (seven amino acid extension “WRNKVAD” at the C-terminal), and NS2 (E69G) proteins. Survival and histology analyses demonstrated that MA-6DK19 was more virulent in mice than WT-6DK19. Conclusion: Our results suggest that these substitutions are involved in the enhanced replication efficiency and virulence of H5N2 AIVs in mammals. Continuing surveillance for H5N2 viruses in poultry that are carrying these mutations is required. Keywords: Avian influenza viruses, H5N2, Mice, Adaptation, Virulence, Replication
Findings Highly pathogenic H5 avian influenza viruses (AIVs) emerged from Asia in 2003 and have caused severe epidemics among poultry and humans [1–4]. Of the 850 human cases reported to the World Health Organization as of April 4, 2016, 449 (52.8 %) were fatal [5]. Given that highly pathogenic H5 AIVs continue to cross into the human population and that humans lack pre-existing immunity to the viruses, there is the possibility that a pandemic human influenza virus will emerge. Live poultry markets (LPMs), sites for the sale and slaughter of domestic poultry in East Asia [6, 7], are major venues for AIV dissemination, influenza virus reassortment, and cross-species transfer of AIVs [6, 8–10]. * Correspondence: [email protected] State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, 310003 Hangzhou, Zhejiang, China
H5N2 AIVs are consistently found in poultry from LPMs [4, 11, 12] and transmission to individuals in frequent contact with infected birds has been well documented [13, 14]. In addition to active surveillance of LPMs for emergent AIVs, it is necessary to understand the adaptive processes that cause H5N2 AIVs to become highly pathogenic (defined as enhanced replication and increased virulence) in mammals. Our laboratory has previously isolated a novel reassortant highly pathogenic H5N2 AIV [A/duck/Zhejiang/ 6DK19/2013 (H5N2) (
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