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J Virol. Amino-acid substitutions in polymerase basic protein 2 gene contributes to the pathogenicity of the novel A/H7N9 influenza virus in mammalian hosts.
[Source: Journal of Virology, full page: (LINK). Abstract, edited.]
Amino-acid substitutions in polymerase basic protein 2 gene contributes to the pathogenicity of the novel A/H7N9 influenza virus in mammalian hosts.
Chris Ka Pun Mok 1,2, Horace Hok Yeung Lee 1,2, Maxime Lestra 2, John Malcolm Nicholls 3, Chi Wai Michael Chan 1, Sin Fun Sia 1, Huachen Zhu 1, Leo Lit Man Poon 1, Yi Guan 1 and Joseph Malik Sriyal Peiris 1,2*
Author Affiliations: <SUP>1</SUP>Centre of Influenza Research, School of Public Health, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong <SUP>2</SUP>HKU-Pasteur Research Pole, School of Public Health, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong <SUP>3</SUP>Department of Pathology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong
Published ahead of print 8 January 2014, doi: 10.1128/JVI.02740-13 <CITE>JVI.02740-13 </CITE>
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<CITE></CITE>ABSTRACT
A novel avian-origin influenza A/H7N9 virus emerged in 2013 to cause more than 130 cases of zoonotic human disease with an overall case fatality of around 30% in cases detected. It has been shown that an amino acid change at the residue E627K of polymerase basic protein 2 (PB2) occurred frequently in the H7N9 isolates obtained from humans but not in viruses isolated from poultry. Although this mutation has been reported to confer increased mammalian pathogenicity in other avian influenza subtypes, it has not been experimentally investigated in the H7N9 virus. In this study, we determined the contribution of the PB2-E627K in H7N9 virus to the pathogenicity in mammalian hosts. In addition, the compensatory role of the other PB2 mutations at positions T271A, Q591K and D701N in H7N9 virus was investigated. We characterized the activity of polymerase complexes with these PB2 mutations and found that they enhance the polymerase activity in human 293T cells. The rescued mutants enhanced growth in mammalian cells in vitro. Mice infected with the H7N9 mutant containing avian signature PB2-627E showed marked decrease of disease severity (weight loss) and pathology compared to mice infected with the wild type strain (PB2-627K) or other PB2 mutants. Also, mutant with the PB2-627E showed lower virus replication and pro-inflammatory cytokine responses in the lungs of the virus-infected mice which may contribute to pathogenicity. Our results suggest that these amino acid substitutions contributes to mouse pathogenicity and mammalian adaptation.
FOOTNOTES
* Corresponding author. Mailing address: HKU-Pasteur Research Pole, 7/F, Hong Kong Jockey Club Building for Interdisciplinary Research,, 5 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region, PR China, Phone: 852-2816 8404, Fax: 852-2872 5782, E-mail: malik@hku.hk
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
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Amino-acid substitutions in polymerase basic protein 2 gene contributes to the pathogenicity of the novel A/H7N9 influenza virus in mammalian hosts.
Chris Ka Pun Mok 1,2, Horace Hok Yeung Lee 1,2, Maxime Lestra 2, John Malcolm Nicholls 3, Chi Wai Michael Chan 1, Sin Fun Sia 1, Huachen Zhu 1, Leo Lit Man Poon 1, Yi Guan 1 and Joseph Malik Sriyal Peiris 1,2*
Author Affiliations: <SUP>1</SUP>Centre of Influenza Research, School of Public Health, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong <SUP>2</SUP>HKU-Pasteur Research Pole, School of Public Health, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong <SUP>3</SUP>Department of Pathology, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong
Published ahead of print 8 January 2014, doi: 10.1128/JVI.02740-13 <CITE>JVI.02740-13 </CITE>
<CITE></CITE>
<CITE></CITE>
<CITE></CITE>ABSTRACT
A novel avian-origin influenza A/H7N9 virus emerged in 2013 to cause more than 130 cases of zoonotic human disease with an overall case fatality of around 30% in cases detected. It has been shown that an amino acid change at the residue E627K of polymerase basic protein 2 (PB2) occurred frequently in the H7N9 isolates obtained from humans but not in viruses isolated from poultry. Although this mutation has been reported to confer increased mammalian pathogenicity in other avian influenza subtypes, it has not been experimentally investigated in the H7N9 virus. In this study, we determined the contribution of the PB2-E627K in H7N9 virus to the pathogenicity in mammalian hosts. In addition, the compensatory role of the other PB2 mutations at positions T271A, Q591K and D701N in H7N9 virus was investigated. We characterized the activity of polymerase complexes with these PB2 mutations and found that they enhance the polymerase activity in human 293T cells. The rescued mutants enhanced growth in mammalian cells in vitro. Mice infected with the H7N9 mutant containing avian signature PB2-627E showed marked decrease of disease severity (weight loss) and pathology compared to mice infected with the wild type strain (PB2-627K) or other PB2 mutants. Also, mutant with the PB2-627E showed lower virus replication and pro-inflammatory cytokine responses in the lungs of the virus-infected mice which may contribute to pathogenicity. Our results suggest that these amino acid substitutions contributes to mouse pathogenicity and mammalian adaptation.
FOOTNOTES
* Corresponding author. Mailing address: HKU-Pasteur Research Pole, 7/F, Hong Kong Jockey Club Building for Interdisciplinary Research,, 5 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region, PR China, Phone: 852-2816 8404, Fax: 852-2872 5782, E-mail: malik@hku.hk
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
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