PT  - JOURNAL ARTICLE
AU  - Yoriyuki Konno
AU  - Izumi Kimura
AU  - Keiya Uriu
AU  - Masaya Fukushi
AU  - Takashi Irie
AU  - Yoshio Koyanagi
AU  - So Nakagawa
AU  - Kei Sato
TI  - SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant
AID  - 10.1101/2020.05.11.088179
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.11.088179
4099  - http://biorxiv.org/content/early/2020/05/12/2020.05.11.088179.short
4100  - http://biorxiv.org/content/early/2020/05/12/2020.05.11.088179.full
AB  - 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 revealed that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of more than 15,000 SARS-CoV-2 sequences identified 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 a possibility of the emergence of natural SARS-CoV-2 quasispecies with extended ORF3b that may exacerbate COVID-19 symptoms.HighlightsORF3b of SARS-CoV-2 and related bat and pangolin viruses is a potent IFN antagonistSARS-CoV-2 ORF3b suppresses IFN induction more efficiently than SARS-CoV orthologThe anti-IFN activity of ORF3b depends on the length of its C-terminusAn ORF3b with increased IFN antagonism was isolated from two severe COVID-19 casesCompeting Interest StatementThe authors have declared no competing interest.