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      PB2-Q591K Mutation Determines the Pathogenicity of Avian H9N2 Influenza Viruses for Mammalian Species

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          Abstract

          Background

          Influenza A subtype H9N2 is widespread and prevalent in poultry. It has repeatedly transmitted zoonotically to cause mild influenza-like illness in humans and is regarded as a potential pandemic candidate. In additon, the six internal genes of H7N9 and H10N8 viruses which caused infection in human in China as well as some of the highly pathogenic H5N1 strains are origined from H9N2. Previous studies have shown that the mammalian adaptation PB2-Q591K contributes to the pathogenicity of H5N1 and H7N9 viruses. However, the role of the PB2-Q591K mutation in H9N2 subtype is still not well understood.

          Methods

          To define and compare the individual role of PB2-Q591K substitution in the PB2 gene segment of H9N2 in relation to polymerase activity, replication competence and the pathogenicity using in vitro and in vivo models.

          Results

          The PB2-Q591K mutation in H9N2 virus enhanced the polymerase activity and virus replication in human NHBE cells when compared to the wild type strain. Mice infected with the PB2 mutant showed significant weight loss, higher virus replication and immune responses in the lungs.

          Conclusions

          Our evidences suggest that the PB2-Q591K, in addition to the -E627K mutation in H9N2 enhanced the pathogenicity in mammalian host.

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          Most cited references 22

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          Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia

          Avian influenza A (H5N1) viruses cause severe disease in humans 1,2 , but the basis for their virulence remains unclear. In vitro and animal studies indicate that high and disseminated viral replication is important for disease pathogenesis 3,4,5 . Laboratory experiments suggest that virus-induced cytokine dysregulation may contribute to disease severity 6,7,8,9 . To assess the relevance of these findings for human disease, we performed virological and immunological studies in 18 individuals with H5N1 and 8 individuals infected with human influenza virus subtypes. Influenza H5N1 infection in humans is characterized by high pharyngeal virus loads and frequent detection of viral RNA in rectum and blood. Viral RNA in blood was present only in fatal H5N1 cases and was associated with higher pharyngeal viral loads. We observed low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in H5N1-infected individuals, particularly in those who died, and these correlated with pharyngeal viral loads. Genetic characterization of H5N1 viruses revealed mutations in the viral polymerase complex associated with mammalian adaptation and virulence. Our observations indicate that high viral load, and the resulting intense inflammatory responses, are central to influenza H5N1 pathogenesis. The focus of clinical management should be on preventing this intense cytokine response, by early diagnosis and effective antiviral treatment. Supplementary information The online version of this article (doi:10.1038/nm1477) contains supplementary material, which is available to authorized users.
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            Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses.

            In 1997, an H5N1 influenza A virus was transmitted from birds to humans in Hong Kong, killing 6 of the 18 people infected. When mice were infected with the human isolates, two virulence groups became apparent. Using reverse genetics, we showed that a mutation at position 627 in the PB2 protein influenced the outcome of infection in mice. Moreover, high cleavability of the hemagglutinin glycoprotein was an essential requirement for lethal infection.
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              Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?

              In 1997, the first documented instance of human respiratory disease and death associated with a purely avian H5N1 influenza virus resulted in an overall case-fatality rate of 33%. The biological basis for the severity of human H5N1 disease has remained unclear. We tested the hypothesis that virus-induced cytokine dysregulation has a role. We used cDNA arrays and quantitative RT-PCR to compare the profile of cytokine gene expression induced by viruses A/HK/486/97 and A/HK/483/97 (both H5N1/97) with that of human H3N2 and H1N1 viruses in human primary monocyte-derived macrophages in vitro. Secretion of tumour necrosis factor alpha (TNF alpha) from macrophages infected with the viruses was compared by ELISA. By use of naturally occurring viral reassortants and recombinant viruses generated by reverse genetic techniques, we investigated the viral genes associated with the TNF-alpha response. The H5N1/97 viruses induced much higher gene transcription of proinflammatory cytokines than did H3N2 or H1N1 viruses, particularly TNF alpha and interferon beta. The concentration of TNF-alpha protein in culture supernatants of macrophages infected with these viruses was similar to that induced by stimulation with Escherichia coli lipopolysaccharide. The non-structural (NS) gene-segment of H5N1/97 viruses contributed to the increase in TNF alpha induced by the virus. The H5N1/97 viruses are potent inducers of proinflammatory cytokines in macrophages, the most notable being TNF alpha. This characteristic may contribute to the unusual severity of human H5N1 disease.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                29 September 2016
                2016
                : 11
                : 9
                Affiliations
                [1 ]Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, GuangZhou, PR China
                [2 ]Centre of Influenza Research, School of Public Health, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, PR China
                [3 ]HKU-Pasteur Research Pole, School of Public Health, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, PR China
                [4 ]State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
                [5 ]Department of Laboratory Medicine, Guangdong No.2 Provincial People’s Hospital, GuangZhou, PR China
                Deutsches Primatenzentrum GmbH—Leibniz-Institut fur Primatenforschung, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: CKPM ZZ.

                • Data curation: CKPM.

                • Formal analysis: CW CKPM ZFY ZZ.

                • Funding acquisition: CKPM ZFY.

                • Investigation: CW HHYL CKPM ZFY ZZ.

                • Methodology: CW HHYL CKPM.

                • Project administration: CW HHYL CKPM.

                • Resources: CKPM ZFY ZZ.

                • Software: CW HHYL.

                • Supervision: CKPM ZZ.

                • Validation: CW CKPM ZZ.

                • Visualization: CW HHYL.

                • Writing – original draft: CW CKPM ZZ.

                • Writing – review & editing: CW CKPM ZZ.

                Article
                PONE-D-16-17829
                10.1371/journal.pone.0162163
                5042486
                27684944
                © 2016 Wang et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 7, Tables: 0, Pages: 16
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100005847, Health and Medical Research Fund;
                Award ID: 12111832
                Award Recipient :
                Funded by: municipal science and technology bureau foundation of guangzhou
                Award ID: 2014Y2-00031
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81471937
                Award Recipient :
                This project was supported by Health and Medical Research Fund (no. 12111832), Municipal Science and Technology Bureau Foundation of Guangzhou (no. 2014Y2-00031) and National Natural Science Foundation of China (no. 81471937).
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