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

PLoS Pathogens

Burkhard Ludewig¹  Friedemann Weber¹  Gjon Blakqori¹  Roland Züst²  Volker Thiel²  Luisa Cervantes-Barragán²  Thomas Kuri³ 

[1] Department of Virology, University of Freiburg, Freiburg, Germany;Research Department, Kantonal Hospital St. Gallen, St. Gallen, Switzerland;Unidad de Investigación Médica en Inmunoquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México City, México

关键词: Viral replication;    Coronaviruses;    SARS coronavirus;    Attenuated vaccines;    Immune response;    Mouse models;    Pathogenesis;    Recombinant vaccines;   

DOI  :  10.1371/journal.ppat.0030109

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY