Stimulation of interferon-β responses by aberrant SARS-CoV-2 small viral RNAs acting as retinoic acid-inducible gene-I agonists

Yasuha Arai; Itaru Yamanaka; Toru Okamoto; Ayana Isobe; Naomi Nakai; Naoko Kamimura; Tatsuya Suzuki; Tomo Daidoji; Takao Ono; Takaaki Nakaya; Kazuhiko Matsumoto; Daisuke Okuzaki; Yohei Watanabe

doi:10.1016/j.isci.2022.105742

Stimulation of interferon-β responses by aberrant SARS-CoV-2 small viral RNAs acting as retinoic acid-inducible gene-I agonists

iScience. 2023 Jan 20;26(1):105742. doi: 10.1016/j.isci.2022.105742. Epub 2022 Dec 7.

Authors

Affiliations

¹ Department of Infectious Diseases, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
² Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
³ Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
⁴ SANKEN, Osaka University, Osaka 567-0047, Japan.
⁵ Single Cell Genomics, Human Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.

Abstract

Patients with severe COVID-19 exhibit a cytokine storm characterized by greatly elevated levels of cytokines. Despite this, the interferon (IFN) response is delayed, contributing to disease progression. Here, we report that SARS-CoV-2 excessively generates small viral RNAs (svRNAs) encoding exact 5' ends of positive-sense genes in human cells in vitro and ex vivo, whereas endemic human coronaviruses (OC43 and 229E) produce significantly fewer similar svRNAs. SARS-CoV-2 5' end svRNAs are RIG-I agonists and induce the IFN-β response in the later stages of infection. The first 60-nt ends bearing duplex structures and 5'-triphosphates are responsible for immune-stimulation. We propose that RIG-I activation by accumulated SARS-CoV-2 5' end svRNAs may contribute to later drive over-exuberant IFN production. Additionally, the differences in the amounts of svRNAs produced and the corresponding IFN response among CoV strains suggest that lower svRNA production during replication may correlate with the weaker immune response seen in less pathogenic CoVs.

Keywords: immunology and virology.