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      A 20-Amino-Acid Deletion in the Neuraminidase Stalk and a Five-Amino-Acid Deletion in the NS1 Protein Both Contribute to the Pathogenicity of H5N1 Avian Influenza Viruses in Mallard Ducks

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          Abstract

          Since 2003, H5N1-subtype avian influenza viruses (AIVs) with both a deletion of 20 amino acids in the stalk of the neuraminidase (NA) glycoprotein (A−) and a deletion of five amino acids at positions 80 to 84 in the non-structural protein NS1 (S−) have become predominant. To understand the influence of these double deletions in the NA and NS1 proteins on the pathogenicity of H5N1-subtype AIVs, we selected A/mallard/Huadong/S/2005 as a parental strain to generate rescued wild-type A−S− and three variants (A−S+ with a five-amino-acid insertion in the NS1 protein, A+S− with a 20-amino-acid insertion in the NA stalk, and A+S+ with insertions in both NA and NS1 proteins) and evaluated their biological characteristics and virulence. The titers of the AIVs with A− and/or S− replicated in DEF cells were higher than that of A+S+, and the A−S− virus exhibited a replication predominance when co-infected with the other variants in DEF cells. In addition, A−S− induced a more significant increase in the expression of immune-related genes in peripheral blood mononuclear cells of mallard ducks in vitro compared with the other variants. Furthermore, an insertion in the NA and/or NS1 proteins of AIVs resulted in a notable decrease in virulence in ducks, as determined by intravenous pathogenicity index, and the two insertions exerted a synergistic effect on the attenuation of pathogenicity in ducks. In addition, compared with A+S+ and A+S−, the A−S+ and A−S− viruses that were introduced via the intranasal inoculation route exhibited a faster replication ability in the lungs of ducks. These data indicate that both the deletions in the NA stalk and the NS1 protein contribute to the high pathogenicity of H5N1 AIVs in ducks.

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          Most cited references44

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          Association of RIG-I with innate immunity of ducks to influenza.

          Ducks and wild waterfowl perpetuate all strains of influenza viruses in nature. In their natural host, influenza viruses typically cause asymptomatic infection and little pathology. Ducks are often resistant to influenza viruses capable of killing chickens. Here, we show that the influenza virus sensor, RIG-I, is present in ducks and plays a role in clearing an influenza infection. We show evidence suggesting that RIG-I may be absent in chickens, providing a plausible explanation for their increased susceptibility to influenza viruses compared with ducks. RIG-I detects RNA ligands derived from uncapped viral transcripts and initiates the IFN response. In this study, we show that the chicken embryonic fibroblast cell line, DF-1, cannot respond to a RIG-I ligand. However, transfection of duck RIG-I into DF-1 cells rescues the detection of ligand and induces IFN-beta promoter activity. Additionally, DF-1 cells expressing duck RIG-I have an augmented IFN response resulting in decreased influenza replication after challenge with either low or highly pathogenic avian influenza virus. Implicating RIG-I in the antiviral response to an infection in vivo, we found that RIG-I expression is induced 200 fold, early in an innate immune response in ducks challenged with the H5N1 virus A/Vietnam/1203/04. Finding this natural disease resistance gene in ducks opens the possibility of increasing influenza resistance through creation of a transgenic chicken.
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            Lethal H5N1 influenza viruses escape host anti-viral cytokine responses.

            The H5N1 influenza viruses transmitted to humans in 1997 were highly virulent, but the mechanism of their virulence in humans is largely unknown. Here we show that lethal H5N1 influenza viruses, unlike other human, avian and swine influenza viruses, are resistant to the antiviral effects of interferons and tumor necrosis factor alpha. The nonstructural (NS) gene of H5N1 viruses is associated with this resistance. Pigs infected with recombinant human H1N1 influenza virus that carried the H5N1 NS gene experienced significantly greater and more prolonged viremia, fever and weight loss than did pigs infected with wild-type human H1N1 influenza virus. These effects required the presence of glutamic acid at position 92 of the NS1 molecule. These findings may explain the mechanism of the high virulence of H5N1 influenza viruses in humans.
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              Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium.

              Influenza virus neuraminidase (NA) plays an essential role in release and spread of progeny virions, following the intracellular viral replication cycle. To test whether NA could also facilitate virus entry into cell, we infected cultures of human airway epithelium with human and avian influenza viruses in the presence of the NA inhibitor oseltamivir carboxylate. Twenty- to 500-fold less cells became infected in drug-treated versus nontreated cultures (P < 0.0001) 7 h after virus application, indicating that the drug suppressed the initiation of infection. These data demonstrate that viral NA plays a role early in infection, and they provide further rationale for the prophylactic use of NA inhibitors.
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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, USA )
                1932-6203
                2014
                17 April 2014
                : 9
                : 4
                : e95539
                Affiliations
                [1]College of Veterinary Medicine, Yangzhou University, Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, P.R. China
                The University of Hong Kong, Hong Kong
                Author notes

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

                Conceived and designed the experiments: YL DP XL. Performed the experiments: YL SC XZ QF ZZ YZ MG SS. Analyzed the data: YL SC DP. Contributed reagents/materials/analysis tools: YL SC. Wrote the paper: YL SC DP XL.

                Article
                PONE-D-13-32239
                10.1371/journal.pone.0095539
                3990698
                24743258
                c8564c5e-dfd9-4bd5-8c45-627e920e4645
                Copyright @ 2014

                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.

                History
                : 4 August 2013
                : 28 March 2014
                Page count
                Pages: 12
                Funding
                This work was supported by the Major National Basic Research Development Program (973 Program) (grant number 2011CB505003), the Jiangsu High School Natural Science Foundation (10KJA230055), the Important National Science & Technology Specific Projects (2012ZX10004214001002), the Special Fund for Agro-scientific Research in the Public Interest (20100312), the National High-Tech Research and Development Program of China (2011AA10A209), the Qing Lan Project, and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions and the Yangzhou University Funding for Scientific Research (2012CXJ081). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Evolutionary Biology
                Organismal Evolution
                Microbial Evolution
                Viral Evolution
                Genetics
                Mutagenesis
                Mutation
                Microbiology
                Medical microbiology
                Microbial pathogens
                Viral pathogens
                Orthomyxoviruses
                Influenza viruses
                Avian influenza A viruses
                Virology
                Viral Transmission and Infection
                Viral Load
                Animal Models of Infection
                Veterinary Science
                Veterinary Diseases
                Veterinary Virology
                Zoonoses
                Medicine and Health Sciences
                Infectious Diseases
                Pathology and Laboratory Medicine
                Pathogens
                Virulence Factors
                Pathogenesis

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                Uncategorized

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