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      Flavivirus NS1: a multifaceted enigmatic viral protein

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          Abstract

          Flaviviruses are emerging arthropod-borne viruses representing an immense global health problem. The prominent viruses of this group include dengue virus, yellow fever virus, Japanese encephalitis virus, West Nile virus tick borne encephalitis virus and Zika Virus. These are endemic in many parts of the world. They are responsible for the illness ranging from mild flu like symptoms to severe hemorrhagic, neurologic and cognitive manifestations leading to death. NS1 is a highly conserved non-structural protein among flaviviruses, which exist in diverse forms. The intracellular dimer form of NS1 plays role in genome replication, whereas, the secreted hexamer plays role in immune evasion. The secreted NS1 has been identified as a potential diagnostic marker for early detection of the infections caused by flaviviruses. In addition to the diagnostic marker, the importance of NS1 has been reported in the development of therapeutics. NS1 based subunit vaccines are at various stages of development. The structural details and diverse functions of NS1 have been discussed in detail in this review.

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          Composition and Three-Dimensional Architecture of the Dengue Virus Replication and Assembly Sites

          Sonja Welsch, Sven Miller, Inés Romero-Brey … (2009)
          Summary Positive-strand RNA viruses are known to rearrange cellular membranes to facilitate viral genome replication. The biogenesis and three-dimensional organization of these membranes and the link between replication and virus assembly sites is not fully clear. Using electron microscopy, we find Dengue virus (DENV)-induced vesicles, convoluted membranes, and virus particles to be endoplasmic reticulum (ER)-derived, and we detect double-stranded RNA, a presumed marker of RNA replication, inside virus-induced vesicles. Electron tomography (ET) shows DENV-induced membrane structures to be part of one ER-derived network. Furthermore, ET reveals vesicle pores that could enable release of newly synthesized viral RNA and reveals budding of DENV particles on ER membranes directly apposed to vesicle pores. Thus, DENV modifies ER membrane structure to promote replication and efficient encapsidation of the genome into progeny virus. This architecture of DENV replication and assembly sites could explain the coordination of distinct steps of the flavivirus replication cycle.
          Article 0 comments Cited 424 times – based on 0 reviews     Review now
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            Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination.

            P. Robert Beatty, Henry Nelson Puerta-Guardo, Sarah S Killingbeck … (2015)
            The four dengue virus serotypes (DENV1 to DENV4) are mosquito-borne flaviviruses that cause up to ~100 million cases of dengue annually worldwide. Severe disease is thought to result from immunopathogenic processes involving serotype cross-reactive antibodies and T cells that together induce vasoactive cytokines, causing vascular leakage that leads to shock. However, no viral proteins have been directly implicated in triggering endothelial permeability, which results in vascular leakage. DENV nonstructural protein 1 (NS1) is secreted and circulates in patients' blood during acute infection; high levels of NS1 are associated with severe disease. We show that inoculation of mice with DENV NS1 alone induces both vascular leakage and production of key inflammatory cytokines. Furthermore, simultaneous administration of NS1 with a sublethal dose of DENV2 results in a lethal vascular leak syndrome. We also demonstrate that NS1 from DENV1, DENV2, DENV3, and DENV4 triggers endothelial barrier dysfunction, causing increased permeability of human endothelial cell monolayers in vitro. These pathogenic effects of physiologically relevant amounts of NS1 in vivo and in vitro were blocked by NS1-immune polyclonal mouse serum or monoclonal antibodies to NS1, and immunization of mice with NS1 from DENV1 to DENV4 protected against lethal DENV2 challenge. These findings add an important and previously overlooked component to the causes of dengue vascular leak, identify a new potential target for dengue therapeutics, and support inclusion of NS1 in dengue vaccines.
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              The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker.

              David Muller, Paul R Young (2013)
              The flavivirus nonstructural glycoprotein NS1 is an enigmatic protein whose structure and mechanistic function have remained somewhat elusive ever since it was first reported in 1970 as a viral antigen circulating in the sera of dengue-infected patients. All flavivirus NS1 genes share a high degree of homology, encoding a 352-amino-acid polypeptide that has a molecular weight of 46-55 kDa, depending on its glycosylation status. NS1 exists in multiple oligomeric forms and is found in different cellular locations: a cell membrane-bound form in association with virus-induced intracellular vesicular compartments, on the cell surface and as a soluble secreted hexameric lipoparticle. Intracellular NS1 co-localizes with dsRNA and other components of the viral replication complex and plays an essential cofactor role in replication. Although this makes NS1 an ideal target for inhibitor design, the precise nature of its cofactor function has yet to be elucidated. A plethora of potential interacting partners have been identified, particularly for the secreted form of NS1, with many being implicated in immune evasion strategies. Secreted and cell-surface-associated NS1 are highly immunogenic and both the proteins themselves and the antibodies they elicit have been implicated in the seemingly contradictory roles of protection and pathogenesis in the infected host. Finally, NS1 is also an important biomarker for early diagnosis of disease. In this article, we provide an overview of these somewhat disparate areas of research, drawing together the wealth of data generated over more than 40 years of study of this fascinating protein. Copyright © 2013 Elsevier B.V. All rights reserved.
              Article 0 comments Cited 187 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Meghana Rastogi: rastogi.m0@gmail.com
                Nikhil Sharma: nikhil@ccmb.res.in
                Sunit Kumar Singh: sunitsingh2000@gmail.com
                Journal
                Journal ID (nlm-ta): Virol J
                Journal ID (iso-abbrev): Virol. J
                Title: Virology Journal
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1743-422X
                Publication date (Electronic): 29 July 2016
                Publication date PMC-release: 29 July 2016
                Publication date Collection: 2016
                Volume: 13
                Electronic Location Identifier: 131
                Affiliations
                [1 ]Institute of Medical Sciences (IMS), Laboratory of Human Molecular Virology & Immunology, Molecular Biology Unit, Faculty of Medicine, Banaras Hindu University, Varanasi, 221005 India
                [2 ]Laboratory of Neurovirology and Inflammation Biology, CSIR-Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Hyderabad, 500007 India
                Article
                Publisher ID: 590
                DOI: 10.1186/s12985-016-0590-7
                PMC ID: 4966872
                PubMed ID: 27473856
                SO-VID: ffe65720-9d31-4954-a39c-5f77c1872d42
                Copyright © © The Author(s). 2016
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 31 May 2016
                Date accepted : 26 July 2016
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2016

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: flavivirus,non-structural proteins,arboviruses,ns1 protein
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: flavivirus, non-structural proteins, arboviruses, ns1 protein

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