Coronavirus non-structural protein 1 is a major pathogenicity factor: implications for the rational design of coronavirus vaccines.
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.
Züst
Roland
R
Research Department, Kantonal Hospital St. Gallen, St. Gallen, Switzerland.
Cervantes-Barragán
Luisa
L
Kuri
Thomas
T
Blakqori
Gjon
G
Weber
Friedemann
F
Ludewig
Burkhard
B
Thiel
Volker
V
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004279:DNA, Viral; D004195:Disease Models, Animal; D015195:Drug Design; D017353:Gene Deletion; D020868:Gene Silencing; D006524:Hepatitis, Viral, Animal / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007370:Interferon Type I / Q000172:deficiency / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D006517:Murine hepatitis virus / Q000276:immunology* / Q000472:pathogenicity*; D011994:Recombinant Proteins / Q000276:immunology; D014613:Vaccines, Attenuated / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014765:Viral Vaccines / Q000276:immunology*; D037521:Virulence Factors / Q000276:immunology*; D014779:Virus Replication
D004279:DNA, Viral; D007370:Interferon Type I; C505227:NSP1 protein, murine hepatitis virus; D011994:Recombinant Proteins; D014613:Vaccines, Attenuated; D017361:Viral Nonstructural Proteins; D014765:Viral Vaccines; D037521:Virulence Factors
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