SARS-CoV-2 ORF3b Is a Potent Interferon Antagonist Whose Activity Is Increased by a Naturally Occurring Elongation Variant

Cell Reports

卷:32

Masaya Fukushi¹  Kei Sato²  Keiya Uriu³  Izumi Kimura³  Yoriyuki Konno³  Yoshio Koyanagi⁴  Takashi Irie⁴  Robert J. Gifford⁵  Daniel Sauter⁶  So Nakagawa⁷ 

[1] Graduate School of Medicine, the University of Tokyo, Tokyo 1130033, Japan;

[2] Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 2591193, Japan;

[3] Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, the University of Tokyo, Tokyo 1088639, Japan;

[4] Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7398511, Japan;

[5] Institute of Molecular Virology, Ulm University Medical Center, Ulm 89081, Germany;

[6] Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 6068507, Japan;

[7] MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G61 1QH, UK;

关键词: SARS-CoV-2;    COVID-19;    ORF3b;    type I interferon;    evolution;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays reveal that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of approximately 17,000 SARS-CoV-2 sequences identify a natural variant in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients but also describe the emergence of natural SARS-CoV-2 quasispecies with an extended ORF3b gene that may potentially affect COVID-19 pathogenesis.

【 授权许可】

Unknown