A live attenuated severe acute respiratory syndrome coronavirus is immunogenic and efficacious in golden Syrian hamsters.

Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA.
Journal of Virology (Impact Factor: 4.65). 09/2008; 82(15):7721-4. DOI: 10.1128/JVI.00304-08
Source: PubMed

ABSTRACT The immunogenicity and protective efficacy of a live attenuated vaccine consisting of a recombinant severe acute respiratory syndrome (SARS) coronavirus lacking the E gene (rSARS-CoV-DeltaE) were studied using hamsters. Hamsters immunized with rSARS-CoV-DeltaE developed high serum-neutralizing antibody titers and were protected from replication of homologous (SARS-CoV Urbani) and heterologous (GD03) SARS-CoV in the upper and lower respiratory tract. rSARS-CoV-DeltaE-immunized hamsters remained active following wild-type virus challenge, while mock-immunized hamsters displayed decreased activity. Despite being attenuated in replication in the respiratory tract, rSARS-CoV-DeltaE is an immunogenic and efficacious vaccine in hamsters.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Coronavirus (CoV) infection is usually detected by cellular sensors, which trigger the activation of the innate immune system. Nevertheless, CoVs have evolved viral proteins that target different signaling pathways to counteract innate immune responses. Some CoV proteins act as antagonists of interferon (IFN) by inhibiting IFN production or signaling, aspects that are briefly addressed in this review. After CoV infection, potent cytokines relevant in controlling virus infections and priming adaptive immune responses are also generated. However, an uncontrolled induction of these proinflammatory cytokines can lead to pathogenesis and disease severity as described for SARS-CoV and MERS-CoV. The cellular pathways mediated by interferon regulatory factor (IRF)-3 and 7, activating transcription factor (ATF)-2/jun, activator protein (AP)-1, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and nuclear factor of activated T cells (NF-AT), are the main drivers of the inflammatory response triggered after viral infections, with NF-κB pathway the most frequently activated. Key CoV proteins involved in the regulation of these pathways and the proinflammatory immune response are revisited in this manuscript. It has been shown that the envelope (E) protein plays a variable role in CoV morphogenesis, depending on the CoV genus, being absolutely essential in some cases (genus α CoVs such as TGEV, and genus β CoVs such as MERS-CoV), but not in others (genus β CoVs such as MHV or SARS-CoV). A comprehensive accumulation of data has shown that the relatively small E protein elicits a strong influence on the interaction of SARS-CoV with the host. In fact, after infection with viruses in which this protein has been deleted, increased cellular stress and unfolded protein responses, apoptosis, and augmented host immune responses were observed. In contrast, the presence of E protein activated a pathogenic inflammatory response that may cause death in animal models and in humans. The modification or deletion of different motifs within E protein, including the transmembrane domain that harbors an ion channel activity, small sequences within the middle region of the carboxy-terminus of E protein, and its most carboxy-terminal end, which contains a PDZ domain-binding motif (PBM) is sufficient to attenuate the virus. Interestingly, a comprehensive collection of SARS-CoVs in which these motifs have been modified elicited full and long-term protection even in old mice, making those deletion mutants promising vaccine candidates. These data indicate that despite its small size, E protein drastically influences the replication of CoVs and their pathogenicity. Although E protein is not essential for CoV genome replication or subgenomic mRNA synthesis, it affects virus morphogenesis, budding, assembly, intracellular trafficking, and virulence. In fact, E protein is responsible in a significant proportion of the inflammasome activation and the associated inflammation elicited by SARS-CoV in the lung parenchyma. This exacerbated inflammation causes edema accumulation leading to acute respiratory distress syndrome (ARDS) and, frequently, to the death of infected animal models or human patients.
    Virus Research 08/2014; DOI:10.1016/j.virusres.2014.07.024 · 2.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Respiratory viruses can cause a wide spectrum of pulmonary disease ranging from mild, upper respiratory tract infections to severe and life-threatening lower respiratory tract infection including development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Viral clearance and subsequent recovery from infection require activation of an effective host immune response; however, many immune effector cells may also cause injury to host tissues. Severe Acute Respiratory Syndrome (SARS) Coronavirus and Middle East Respiratory Syndrome (MERS) Coronavirus cause severe infection of the lower respiratory tract with 10% and 35% overall mortality rates respectively; however, >50% mortality rates are seen in the aged and immunosuppressed populations. While these viruses are susceptible to interferon treatment in vitro, they both encode numerous genes that allow for successful evasion of the host immune system until after high virus titres have been achieved. In this review we discuss the importance of the innate immune response and the development of lung pathology following human coronavirus infection.
    The Journal of Pathology 09/2014; 235(2). DOI:10.1002/path.4454 · 7.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Coronaviruses (CoVs) infect humans and many animal species, and are associated with respiratory, enteric, hepatic, and central nervous system diseases. The large size of the CoV genome and the instability of some CoV replicase gene sequences during its propagation in bacteria, represent serious obstacles for the development of reverse genetic systems similar to those used for smaller positive sense RNA viruses.To overcome these limitations, several alternatives to more conventional plasmid-based approaches have been established in the last thirteen years. In this report, we briefly reviewand discuss the different reverse genetic systemsdeveloped for CoVs, paying special attention tothe severe acute respiratory syndrome CoV (SARS-CoV).
    Virus Research 06/2014; DOI:10.1016/j.virusres.2014.05.026 · 2.83 Impact Factor

Full-text (2 Sources)

Available from
Feb 18, 2015