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Open AccessArticle

H7N9 Influenza Virus Containing a Polybasic HA Cleavage Site Requires Minimal Host Adaptation to Obtain a Highly Pathogenic Disease Phenotype in Mice

1
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2, Canada
2
National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, MB R3E 3M4, Canada
3
Department of Medical Microbiology and Infectious Diseases, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB R3E 0J9, Canada
4
Institut Pasteur of Shanghai, Chinese Academy of Sciences, Life Science Research Building 320 Yueyang Road, Xuhui District, Shanghai 200031, China
5
Département de microbiologie-infectiologie et d’immunologie, Université Laval, 1050 avenue de la Médecine, QC G1V 0A6, Canada
6
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), Chinese Academy of Sciences, Beijing 100101, China
*
Author to whom correspondence should be addressed.
Viruses 2020, 12(1), 65; https://doi.org/10.3390/v12010065
Received: 14 September 2019 / Revised: 23 December 2019 / Accepted: 3 January 2020 / Published: 5 January 2020
(This article belongs to the Special Issue Pathogenesis of Emerging Viral Infections)
Low pathogenic avian influenza (LPAI) H7N9 viruses have recently evolved to gain a polybasic cleavage site in the hemagglutinin (HA) protein, resulting in variants with increased lethality in poultry that meet the criteria for highly pathogenic avian influenza (HPAI) viruses. Both LPAI and HPAI variants can cause severe disease in humans (case fatality rate of ~40%). Here, we investigated the virulence of HPAI H7N9 viruses containing a polybasic HA cleavage site (H7N9-PBC) in mice. Inoculation of mice with H7N9-PBC did not result in observable disease; however, mice inoculated with a mouse-adapted version of this virus, generated by a single passage in mice, caused uniformly lethal disease. In addition to the PBC site, we identified three other mutations that are important for host-adaptation and virulence in mice: HA (A452T), PA (D347G), and PB2 (M483K). Using reverse genetics, we confirmed that the HA mutation was the most critical for increased virulence in mice. Our study identifies additional disease determinants in a mammalian model for HPAI H7N9 virus. Furthermore, the ease displayed by the virus to adapt to a new host highlights the potential for H7N9-PBC viruses to rapidly acquire mutations that may enhance their risk to humans or other animal species. View Full-Text
Keywords: HPAI; H7N9; influenza virus; mammalian adaptation; mice; polybasic HA HPAI; H7N9; influenza virus; mammalian adaptation; mice; polybasic HA
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Chan, M.; Leung, A.; Hisanaga, T.; Pickering, B.; Griffin, B.D.; Vendramelli, R.; Tailor, N.; Wong, G.; Bi, Y.; Babiuk, S.; Berhane, Y.; Kobasa, D. H7N9 Influenza Virus Containing a Polybasic HA Cleavage Site Requires Minimal Host Adaptation to Obtain a Highly Pathogenic Disease Phenotype in Mice. Viruses 2020, 12, 65.

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