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
Affiliations
Yasuha Arai
Department of Infectious Diseases, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
Itaru Yamanaka
Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Toru Okamoto
Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Ayana Isobe
Department of Infectious Diseases, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
Naomi Nakai
Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Naoko Kamimura
Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Tatsuya Suzuki
Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Tomo Daidoji
Department of Infectious Diseases, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
Takao Ono
SANKEN, Osaka University, Osaka 567-0047, Japan
Takaaki Nakaya
Department of Infectious Diseases, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
Kazuhiko Matsumoto
SANKEN, Osaka University, Osaka 567-0047, Japan
Daisuke Okuzaki
Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; Single Cell Genomics, Human Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Yohei Watanabe
Department of Infectious Diseases, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; Corresponding author
Summary: 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.
