Wednesday, May 27, 2020

The Fight Between CoV2 ORF3b and Interferon.

SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant.

Yoriyuki Konno, Izumi Kimura, Keiya Uriu, Masaya Fukushi, Takashi Irie, Yoshio Koyanagi, So Nakagawa, Kei Sato
doi: https://doi.org/10.1101/2020.05.11.088179
This article is a preprint and has not been certified by peer review [what does this mean?].

Abstract

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 quasi species with extended ORF3b that may exacerbate COVID-19 symptoms.
Highlights
  • ORF3b of SARS-CoV-2 and related bat and Pangolin viruses is a potent IFN antagonist
  • SARS-CoV-2 ORF3b suppresses IFN induction more efficiently than SARS-CoV ortholog
  • The anti-IFN activity of ORF3b depends on the length of its C-terminus
  • An ORF3b with increased IFN antagonism was isolated from two severe COVID-19 cases

Competing Interest Statement

The authors have declared no competing interest.
Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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