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      Coronavirus Non-Structural Protein 1 Is a Major Pathogenicity Factor: Implications for the Rational Design of Coronavirus Vaccines

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          Abstract

          Attenuated viral vaccines can be generated by targeting essential pathogenicity factors. We report here the rational design of an attenuated recombinant coronavirus vaccine based on a deletion in the coding sequence of the non-structural protein 1 (nsp1). In cell culture, nsp1 of mouse hepatitis virus (MHV), like its SARS-coronavirus homolog, strongly reduced cellular gene expression. The effect of nsp1 on MHV replication in vitro and in vivo was analyzed using a recombinant MHV encoding a deletion in the nsp1-coding sequence. The recombinant MHV nsp1 mutant grew normally in tissue culture, but was severely attenuated in vivo. Replication and spread of the nsp1 mutant virus was restored almost to wild-type levels in type I interferon (IFN) receptor-deficient mice, indicating that nsp1 interferes efficiently with the type I IFN system. Importantly, replication of nsp1 mutant virus in professional antigen-presenting cells such as conventional dendritic cells and macrophages, and induction of type I IFN in plasmacytoid dendritic cells, was not impaired. Furthermore, even low doses of nsp1 mutant MHV elicited potent cytotoxic T cell responses and protected mice against homologous and heterologous virus challenge. Taken together, the presented attenuation strategy provides a paradigm for the development of highly efficient coronavirus vaccines.

          Author Summary

          Prevention of viral diseases by vaccination aims for controlled induction of protective immune responses against viral pathogens. Live viral vaccines consist of attenuated, replication-competent viruses that are believed to be superior in the induction of broad immune responses, including cell-mediated immunity. The recent proceedings in the area of virus reverse genetics allows for the rational design of recombinant vaccines by targeting, i.e., inactivating, viral pathogenicity factors. For coronaviruses, a major pathogenicity factor has now been identified. The effect of coronavirus non-structural protein 1 on pathogenicity has been analyzed in a murine model of coronavirus infection. By deleting a part of this protein, a recombinant virus has been generated that is greatly attenuated in vivo, while retaining immunogenicity. In particular, the mutant virus retained the ability to replicate in professional antigen-presenting cells and fulfilled an important requirement of a promising vaccine candidate: the induction of a protective long-lasting, antigen-specific cellular immune response. This study has implications for the rational design of live attenuated coronavirus vaccines aimed at preventing coronavirus-induced diseases of veterinary and medical importance, including the potentially lethal severe acute respiratory syndrome.

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          Most cited references38

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          Characterization of a novel coronavirus associated with severe acute respiratory syndrome.

          P Rota (2003)
          In March 2003, a novel coronavirus (SARS-CoV) was discovered in association with cases of severe acute respiratory syndrome (SARS). The sequence of the complete genome of SARS-CoV was determined, and the initial characterization of the viral genome is presented in this report. The genome of SARS-CoV is 29,727 nucleotides in length and has 11 open reading frames, and its genome organization is similar to that of other coronaviruses. Phylogenetic analyses and sequence comparisons showed that SARS-CoV is not closely related to any of the previously characterized coronaviruses.
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            RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.

            Double-stranded RNA (dsRNA) produced during viral replication is believed to be the critical trigger for activation of antiviral immunity mediated by the RNA helicase enzymes retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We showed that influenza A virus infection does not generate dsRNA and that RIG-I is activated by viral genomic single-stranded RNA (ssRNA) bearing 5'-phosphates. This is blocked by the influenza protein nonstructured protein 1 (NS1), which is found in a complex with RIG-I in infected cells. These results identify RIG-I as a ssRNA sensor and potential target of viral immune evasion and suggest that its ability to sense 5'-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.
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              Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus.

              The severe acute respiratory syndrome (SARS), caused by a novel coronavirus (SARS-CoV), resulted in substantial morbidity, mortality, and economic losses during the 2003 epidemic. While SARS-CoV infection has not recurred to a significant extent since 2003, it still remains a potential threat. Understanding of SARS and development of therapeutic approaches have been hampered by the absence of an animal model that mimics the human disease and is reproducible. Here we show that transgenic mice that express the SARS-CoV receptor (human angiotensin-converting enzyme 2 [hACE2]) in airway and other epithelia develop a rapidly lethal infection after intranasal inoculation with a human strain of the virus. Infection begins in airway epithelia, with subsequent alveolar involvement and extrapulmonary virus spread to the brain. Infection results in macrophage and lymphocyte infiltration in the lungs and upregulation of proinflammatory cytokines and chemokines in both the lung and the brain. This model of lethal infection with SARS-CoV should be useful for studies of pathogenesis and for the development of antiviral therapies.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                ppat
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                August 2007
                10 August 2007
                : 3
                : 8
                : e109
                Affiliations
                [1 ] Research Department, Kantonal Hospital St. Gallen, St. Gallen, Switzerland
                [2 ] Unidad de Investigación Médica en Inmunoquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México City, México
                [3 ] Department of Virology, University of Freiburg, Freiburg, Germany
                National Institutes of Health, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: volker.thiel@ 123456kssg.ch
                Article
                07-PLPA-RA-0063R3 plpa-03-08-04
                10.1371/journal.ppat.0030109
                1941747
                17696607
                0b87e74d-1c70-4703-b920-36931d22e095
                Copyright: © 2007 Züst 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.
                History
                : 2 February 2007
                : 12 June 2007
                Page count
                Pages: 11
                Categories
                Research Article
                Immunology
                Infectious Diseases
                Virology
                Viruses
                Mus (Mouse)
                Homo (Human)
                Mammals
                Custom metadata
                Züst R, Cervantes-Barragán L, Kuri T, Blakqori G, Weber F, et al. (2007) Coronavirus non-structural protein 1 is a major pathogenicity factor: Implications for the rational design of coronavirus vaccines. PLoS Pathog 3(8): e109. doi: 10.1371/journal.ppat.0030109

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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