Expression of the readthrough transcript CiDRE in alveolar macrophages boosts SARS-CoV-2 susceptibility and promotes COVID-19 severity

Yuichi Mitsui; Tatsuya Suzuki; Kanako Kuniyoshi; Jun Inamo; Kensuke Yamaguchi; Mariko Komuro; Junya Watanabe; Mio Edamoto; Songling Li; Tsukasa Kouno; Seiya Oba; Tadashi Hosoya; Kentaro Masuhiro; Yujiro Naito; Shohei Koyama; Nobuo Sakaguchi; Daron M Standley; Jay W Shin; Shizuo Akira; Shinsuke Yasuda; Yasunari Miyazaki; Yuta Kochi; Atsushi Kumanogoh; Toru Okamoto; Takashi Satoh

doi:10.1016/j.immuni.2023.06.013

Expression of the readthrough transcript CiDRE in alveolar macrophages boosts SARS-CoV-2 susceptibility and promotes COVID-19 severity

Immunity. 2023 Aug 8;56(8):1939-1954.e12. doi: 10.1016/j.immuni.2023.06.013. Epub 2023 Jul 12.

Authors

Yuichi Mitsui¹, Tatsuya Suzuki², Kanako Kuniyoshi³, Jun Inamo⁴, Kensuke Yamaguchi⁴, Mariko Komuro³, Junya Watanabe³, Mio Edamoto³, Songling Li⁵, Tsukasa Kouno⁶, Seiya Oba⁷, Tadashi Hosoya⁷, Kentaro Masuhiro⁸, Yujiro Naito⁸, Shohei Koyama⁸, Nobuo Sakaguchi⁹, Daron M Standley⁵, Jay W Shin⁶, Shizuo Akira¹⁰, Shinsuke Yasuda⁷, Yasunari Miyazaki¹¹, Yuta Kochi⁴, Atsushi Kumanogoh⁸, Toru Okamoto¹², Takashi Satoh¹³

Affiliations

¹ Department of Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
² Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; Department of Microbiology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
³ Department of Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan.
⁴ Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan.
⁵ Laboratory of Systems Immunology, World Premier Institute Immunology Frontier Research Center, WPI-IFReC, Osaka University, Osaka 565-0871, Japan.
⁶ RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan.
⁷ Department of Rheumatology, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan.
⁸ Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
⁹ Innate Cell Therapy Inc., Osaka 530-0017, Japan.
¹⁰ Innate Cell Therapy Inc., Osaka 530-0017, Japan; Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center, WPI-IFReC, Osaka University, Osaka 565-0871, Japan.
¹¹ Department of Respiratory Medicine, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan.
¹² Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; Center for Infectious Disease Education and Research, Osaka University, Osaka 565-0871, Japan; Department of Microbiology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
¹³ Department of Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan; Innate Cell Therapy Inc., Osaka 530-0017, Japan. Electronic address: satoh.mbch@tmd.ac.jp.

PMID: 37442134
DOI: 10.1016/j.immuni.2023.06.013

Abstract

Lung infection during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin-I-converting enzyme 2 (ACE2) receptor induces a cytokine storm. However, the precise mechanisms involved in severe COVID-19 pneumonia are unknown. Here, we showed that interleukin-10 (IL-10) induced the expression of ACE2 in normal alveolar macrophages, causing them to become vectors for SARS-CoV-2. The inhibition of this system in hamster models attenuated SARS-CoV-2 pathogenicity. Genome-wide association and quantitative trait locus analyses identified a IFNAR2-IL10RB readthrough transcript, COVID-19 infectivity-enhancing dual receptor (CiDRE), which was highly expressed in patients harboring COVID-19 risk variants at the IFNAR2 locus. We showed that CiDRE exerted synergistic effects via the IL-10-ACE2 axis in alveolar macrophages and functioned as a decoy receptor for type I interferons. Collectively, our data show that high IL-10 and CiDRE expression are potential risk factors for severe COVID-19. Thus, IL-10R and CiDRE inhibitors might be useful COVID-19 therapies.

Keywords: M2c macrophage polarization; SARS-CoV-2; active readthrough transcript; hybrid receptor: CiDRE; innate immunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin-Converting Enzyme 2 / genetics
COVID-19* / genetics
Genome-Wide Association Study
Humans
Interleukin-10 / genetics
Macrophages, Alveolar / metabolism
Peptidyl-Dipeptidase A / metabolism
SARS-CoV-2

Substances

Angiotensin-Converting Enzyme 2
Interleukin-10
Peptidyl-Dipeptidase A