Coronavirus non-structural protein 1 is a major pathogenicity factor : implications for the rational design of coronavirus vaccines
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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.
Zust , R , Cervantes-Barragan , L , Kuri , T , Blakqori , G , Weber , F , Ludewig , B & Thiel , V 2007 , ' Coronavirus non-structural protein 1 is a major pathogenicity factor : implications for the rational design of coronavirus vaccines ' PLoS Pathogens , vol 3 , no. 8 , e109 . DOI: 10.1371/journal.ppat.0030109
© 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.
DescriptionZust, Roland Cervantes-Barragan, Luisa Kuri, Thomas Blakqori, Gjon Weber, Friedemann Ludewig, Burkhard Thiel, Volker 5 R21 AI062246/AI/United States NIAID Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States PLoS pathogens PLoS Pathog. 2007 Aug 10;3(8):e109.
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