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Nipah Virus - Mechanisms of Infection

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  • Nipah Virus - Mechanisms of Infection

    Abstract


    Journal of Virology, November 2010, p. 10965-10973, Vol. 84, No. 21
    0022-538X/10/$012.00+0 doi:10.1128/JVI.01335-10
    Copyright ? 2010, American Society for Microbiology. All Rights Reserved.


    Novel Nipah Virus Immune-Antagonism Strategy Revealed by Experimental and Computational Study ,
    Jeremy Seto,1,2, Liang Qiao,1,2, Carolin A. Guenzel,3, Sa Xiao,3,? Megan L. Shaw,3 Fernand Hayot,1,2 and Stuart C. Sealfon1,2*
    Center for Translational Systems Biology,1 Departments of Neurology,2 Microbiology, Mount Sinai School of Medicine, New York, New York 100293

    Received 23 June 2010/ Accepted 7 August 2010

    Nipah virus is an emerging pathogen that causes severe disease in humans. It expresses several antagonist proteins that subvert the immune response and that may contribute to its pathogenicity. Studies of its biology are difficult due to its high pathogenicity and requirement for biosafety level 4 containment. We integrated experimental and computational methods to elucidate the effects of Nipah virus immune antagonists. Individual Nipah virus immune antagonists (phosphoprotein and V and W proteins) were expressed from recombinant Newcastle disease viruses, and the responses of infected human monocyte-derived dendritic cells were determined. We developed an ordinary differential equation model of the infectious process that that produced results with a high degree of correlation with these experimental results. In order to simulate the effects of wild-type virus, the model was extended to incorporate published experimental data on the time trajectories of immune-antagonist production. These data showed that the RNA-editing mechanism utilized by the wild-type Nipah virus to produce immune antagonists leads to a delay in the production of the most effective immune antagonists, V and W. Model simulations indicated that this delay caused a disconnection between attenuation of the antiviral response and suppression of inflammation. While the antiviral cytokines were efficiently suppressed at early time points, some early inflammatory cytokine production occurred, which would be expected to increase vascular permeability and promote virus spread and pathogenesis. These results suggest that Nipah virus has evolved a unique immune-antagonist strategy that benefits from controlled expression of multiple antagonist proteins with various potencies.

  • #2
    Re: Nipah Virus - Mechanisms of Infection

    Abstract
    Journal of Virology, August 2009, p. 7828-7841, Vol. 83, No. 16

    Nipah Virus Sequesters Inactive STAT1 in the Nucleus via a P Gene-Encoded Mechanism
    Michael J. Ciancanelli,1 Valentina A. Volchkova,2,3,4,5 Megan L. Shaw,1 Viktor E. Volchkov,2,3,4,5* and Christopher F. Basler1*
    Received 17 December 2008/ Accepted 12 May 2009

    The Nipah virus (NiV) phosphoprotein (P) gene encodes the C, P, V, and W proteins. P, V, and W, have in common an amino-terminal domain sufficient to bind STAT1, inhibiting its interferon (IFN)-induced tyrosine phosphorylation. P is also essential for RNA-dependent RNA polymerase function. C is encoded by an alternate open reading frame (ORF) within the common amino-terminal domain. Mutations within residues 81 to 113 of P impaired its polymerase cofactor function, as assessed by a minireplicon assay, but these mutants retained STAT1 inhibitory function. Mutations within the residue 114 to 140 region were identified that abrogated interaction with and inhibition of STAT1 by P, V, and W without disrupting P polymerase cofactor function. Recombinant NiVs were then generated. A G121E mutation, which abrogated inhibition of STAT1, was introduced into a C protein knockout background (Cko) because the mutation would otherwise also alter the overlapping C ORF. In cell culture, relative to the wild-type virus, the Cko mutation proved attenuating but the G121E mutant virus replicated identically to the Cko virus. In cells infected with the wild-type and Cko viruses, STAT1 was nuclear despite the absence of tyrosine phosphorylation. This latter observation mirrors what has been seen in cells expressing NiV W. In the G121E mutant virus-infected cells, STAT1 was not phosphorylated and was cytoplasmic in the absence of IFN stimulation but became tyrosine phosphorylated and nuclear following IFN addition. These data demonstrate that the gene for NiV P encodes functions that sequester inactive STAT1 in the nucleus, preventing its activation and suggest that the W protein is the dominant inhibitor of STAT1 in NiV-infected cells.

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    • #3
      Re: Nipah Virus - Mechanisms of Infection



      Transmission of Human Infection with Nipah Virus
      James M. Hughes, Section Editor and Mary E. Wilson, Section Editor
      + Author Affiliations
      Stephen P. Luby1,2,*, Emily S. Gurley1, and M. Jahangir Hossain1

      Abstract
      Nipah virus (NiV) is a paramyxovirus whose reservoir host is fruit bats of the genus Pteropus . Occasionally the virus is introduced into human populations and causes severe illness characterized by encephalitis or respiratory disease. The first outbreak of NiV was recognized in Malaysia, but 8 outbreaks have been reported from Bangladesh since 2001. The primary pathways of transmission from bats to people in Bangladesh are through contamination of raw date palm sap by bats with subsequent consumption by humans and through infection of domestic animals (cattle, pigs, and goats), presumably from consumption of food contaminated with bat saliva or urine with subsequent transmission to people. Approximately one-half of recognized Nipah case patients in Bangladesh developed their disease following person-to-person transmission of the virus. Efforts to prevent transmission should focus on decreasing bat access to date palm sap and reducing family members' and friends' exposure to infected patients' saliva.
      Received May 1, 2009.

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      • #4
        Re: Nipah Virus - Mechanisms of Infection

        Nipah virus: Phylogeny and replication[PDF] from neurologyasia.org

        LY Chang? - Neurology Asia, 2009 - neurologyasia.org

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        • #5
          Re: Nipah Virus - Mechanisms of Infection

          Olivier Pernet, Christine Pohl, Michelle Ainouze, Hasan Kweder, Robin Buckland
          INSERM, Virologie Humaine, Lyon, France
          Neurology Asia 2009; 14 : 71 ? 72

          Nipah virus entry into the host cell does not occur by fusion at the plasma membrane but by the endocytic mechanism of macropinocytosis

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          • #6
            Re: Nipah Virus - Mechanisms of Infection

            Collective licensing pioneer CCC helps you integrate, access, and share information through licensing, content, software and professional services.


            The Nonstructural Proteins of Nipah Virus Play a Key Role in Pathogenicity in Experimentally Infected Animals

            Abstract
            Nipah virus (NiV) P gene encodes P protein and three accessory proteins (V, C and W). It has been reported that all four P gene products have IFN antagonist activity when the proteins were transiently expressed. However, the role of those accessory proteins in natural infection with NiV remains unknown. We generated recombinant NiVs lacking V, C or W protein, rNiV(V2), rNiV(C2), and rNiV(W2), respectively, to analyze the functions of these proteins in infected cells and the implications in in vivo pathogenicity. All the recombinants grew well in cell culture, although the maximum titers of
            rNiV(V2) and rNiV(C2) were lower than the other recombinants. The rNiV(V2), rNiV(C2) and rNiV(W2) suppressed the IFN response as well as the parental rNiV, thereby indicating that the lack of each accessory protein does not significantly affect the inhibition of IFN signaling in infected cells. In experimentally infected golden hamsters, rNiV(V2) and rNiV(C2) but not
            the rNiV(W2) virus showed a significant reduction in virulence. These results suggest that V and C proteins play key roles in NiV pathogenicity, and the roles are independent of their IFN-antagonist activity. This is the first report that identifies the molecular determinants of NiV in pathogenicity in vivo.

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            • #7
              Re: Nipah Virus - Mechanisms of Infection



              A Neutralizing Human Monoclonal Antibody Protects against Lethal Disease in a New Ferret Model of Acute Nipah Virus Infection

              Nipah virus and Hendra virus are closely related and highly pathogenic zoonoses whose primary natural reservoirs are several species of Pteropus fruit bats. Both Nipah and Hendra viruses can cause severe and often fatal disease in a variety of mammalian hosts, including humans. The henipaviruses are categorized as biosafety level 4 (BSL-4) agents, which has limited the development of animal models and the testing of potential therapeutics and vaccine countermeasures. We show here a new ferret model of Nipah virus pathogenesis in which the underlying pathology closely mirrors the illness seen in Nipah virus-infected humans, including both respiratory and neurological disease. We also show that m102.4, a cross-reactive neutralizing human monoclonal antibody that targets the viral attachment glycoprotein, completely protected ferrets from disease when given ten hours after a lethal Nipah virus challenge. This study is the first successful and viable post-exposure passive antibody therapy for Nipah virus using a human monoclonal antibody.

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              • #8
                Re: Nipah Virus - Mechanisms of Infection



                Paramyxovirus Disruption of Interferon Signal Transduction: STATus Report

                RNA viruses in the paramyxovirus family have evolved a number of strategies to escape host cell surveillance and antiviral responses. One mechanism exploited by a number of viruses in this family is direct targeting of cytokine-inducible transcription regulators in the STAT family. Diverse members of this large virus family effectively suppress STAT signaling by the actions of their V proteins, or the related proteins derived from alternate viral mRNAs. These viral proteins have distinct means of targeting STATs, resulting in a variety of negative effects on STATs and their signal transduction. Recent developments in understanding STAT targeting will be reviewed.

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