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      A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease

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          Abstract

          Live-attenuated RNA virus vaccines are efficacious but subject to reversion to virulence. Among RNA viruses, replication fidelity is recognized as a key determinant of virulence and escape from antiviral therapy; increased fidelity is attenuating for some viruses. Coronavirus replication fidelity is approximately 20-fold greater than that of other RNA viruses and is mediated by a 3′-5′ exonuclease activity (ExoN) that likely functions in RNA proofreading. In this study, we demonstrate that engineered inactivation of SARS-CoV ExoN activity results in a stable mutator phenotype with profoundly decreased fidelity in vivo and attenuation of pathogenesis in young, aged, and immunocompromised mouse models of human SARS. The ExoN inactivation genotype and mutator phenotype are stable and do not revert to virulence, even after serial passage or long-term persistent infection in vivo. Our approach represents a strategy with potential for broad applications for the stable attenuation of coronaviruses and possibly other RNA viruses.

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          Global trends in emerging infectious diseases

          Kate E. Jones, Nikkita G Patel, Marc A. Levy … (2008)
          The next new disease Emerging infectious diseases are a major threat to health: AIDS, SARS, drug-resistant bacteria and Ebola virus are among the more recent examples. By identifying emerging disease 'hotspots', the thinking goes, it should be possible to spot health risks at an early stage and prepare containment strategies. An analysis of over 300 examples of disease emerging between 1940 and 2004 suggests that these hotspots can be accurately mapped based on socio-economic, environmental and ecological factors. The data show that the surveillance effort, and much current research spending, is concentrated in developed economies, yet the risk maps point to developing countries as the more likely source of new diseases. Supplementary information The online version of this article (doi:10.1038/nature06536) contains supplementary material, which is available to authorized users.
          Article 0 comments Cited 1214 times – based on 0 reviews     Review now
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            Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection.

            Vincent Cheng, Susanna Lau, Patrick C. Y. Woo … (2007)
            Before the emergence of severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) in 2003, only 12 other animal or human coronaviruses were known. The discovery of this virus was soon followed by the discovery of the civet and bat SARS-CoV and the human coronaviruses NL63 and HKU1. Surveillance of coronaviruses in many animal species has increased the number on the list of coronaviruses to at least 36. The explosive nature of the first SARS epidemic, the high mortality, its transient reemergence a year later, and economic disruptions led to a rush on research of the epidemiological, clinical, pathological, immunological, virological, and other basic scientific aspects of the virus and the disease. This research resulted in over 4,000 publications, only some of the most representative works of which could be reviewed in this article. The marked increase in the understanding of the virus and the disease within such a short time has allowed the development of diagnostic tests, animal models, antivirals, vaccines, and epidemiological and infection control measures, which could prove to be useful in randomized control trials if SARS should return. The findings that horseshoe bats are the natural reservoir for SARS-CoV-like virus and that civets are the amplification host highlight the importance of wildlife and biosecurity in farms and wet markets, which can serve as the source and amplification centers for emerging infections.
            Article 0 comments Cited 287 times – based on 0 reviews     Review now
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              Recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission.

              Rachel Graham, Ralph Baric (2010)
              Over the past 30 years, several cross-species transmission events, as well as changes in virus tropism, have mediated significant animal and human diseases. Most notable is severe acute respiratory syndrome (SARS), a lower respiratory tract disease of humans that was first reported in late 2002 in Guangdong Province, China. The disease, which quickly spread worldwide over a period of 4 months spanning late 2002 and early 2003, infected over 8,000 individuals and killed nearly 800 before it was successfully contained by aggressive public health intervention strategies. A coronavirus (SARS-CoV) was identified as the etiological agent of SARS, and initial assessments determined that the virus crossed to human hosts from zoonotic reservoirs, including bats, Himalayan palm civets (Paguma larvata), and raccoon dogs (Nyctereutes procyonoides), sold in exotic animal markets in Guangdong Province. In this review, we discuss the molecular mechanisms that govern coronavirus cross-species transmission both in vitro and in vivo, using the emergence of SARS-CoV as a model. We pay particular attention to how changes in the Spike attachment protein, both within and outside of the receptor binding domain, mediate the emergence of coronaviruses in new host populations.
              Article 0 comments Cited 208 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9502015
                Journal ID (pubmed-jr-id): 8791
                Journal ID (nlm-ta): Nat Med
                Journal ID (iso-abbrev): Nat. Med.
                Title: Nature medicine
                ISSN (Print): 1078-8956
                ISSN (Electronic): 1546-170X
                Publication date Nihms-submitted: 18 September 2012
                Publication date (Electronic): 11 November 2012
                Publication date (Print): December 2012
                Publication date PMC-release: 01 June 2013
                Volume: 18
                Issue: 12
                Pages: 1820-1826
                Affiliations
                [1 ]Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
                [2 ]Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
                [3 ]Departments of Pediatrics and Pathology, Microbiology, & Immunology, Vanderbilt University, Nashville, TN, 37232, USA
                Author notes
                [* ]Corresponding Author: Ralph S. Baric, Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, 2105D McGavran-Greenberg Hall, CB 7435, Chapel Hill, NC 27599-7435, Phone: (919) 966-3895, Fax: (919) 966-0584, rbaric@ 123456email.unc.edu
                Article
                Manuscript ID: NIHMS408115
                DOI: 10.1038/nm.2972
                PMC ID: 3518599
                PubMed ID: 23142821
                SO-VID: 713c3fee-a19d-4f29-9d48-acf249f5e477
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: U54 AI057157 || AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI075297 || AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: F32 AI080148 || AI
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                Subject: Article

                ScienceOpen disciplines: Medicine
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                ScienceOpen disciplines: Medicine

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