CiDRE M2c Macrophages Hijacked by SARS-CoV-2 Cause COVID-19 Severity

Infection of the lungs with 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 coronavirus disease 2019 (COVID-19) pneumonia are unknown. Here, we show that interleukin-10 (IL-10) changed normal alveolar macrophages into ACE2-expressing M2c-type macrophages that functioned as spreading vectors for SARS-CoV-2 infection. The inhibition of this system attenuated SARS-CoV-2 pathogenicity. Furthermore, genome-wide association and quantitative trait locus analyses identified novel mRNA transcripts, COVID-19 infectivity enhancing dual receptor (CiDRE), are highly expressed in patients harboring COVID-19 risk variants in the IFNAR2/IL10RB locus. This unique receptor has synergistic effects within the IL-10-ACE2 system in macrophages and works as a decoy receptor for type I interferon. Collectively, the IL-10 concentration and CiDRE expression levels are potential risk factors that predict COVID-19 severity and IL-10R and CiDRE inhibitors might be useful COVID-19 therapies.Funding Information: This work was supported by Innate Cell Therapy Co., Ltd. This work was supported by the Japan Science and Technology Agency (JST) by funding with a Grant-in-Aid for Transformative Research Areas B (22H05060 and 22H05061) and Grant-in-Aid for Scientific Research on Innovative Areas (18H05032). This work was supported by the Japan Agency for Medical Research and Development (AMED); Research Program Immunology and Allergy under grant number 21ek0410083h0002 and the Research Program on Hepatitis (18fk0310106h0002 and 18fk0210041h0001). This work was also supported by the Takeda Hosho Grants for Research in Medicine and the Visionary Research Fund from the Takeda Science Foundation, JST Moonshot R&D under Grant Number JPMJMS2024, Grant-in-Aids for Scientific Research (B) (22H02597), Grant-in-Aid for Challenging Research (21K19501) from the MEXT of Japan, and a grant from Medical Research Center Initiative for High Depth Omics.Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: The study protocols were approved by the ethical committees of Tokyo Medical and Dental University (A2021-275C and A2021-294A). All animal experiments with SARS-CoV-2 were performed in Animal Biosafety Level 3 (ABSL3) facilities at the Research Institute for Microbial Diseases, Osaka University. The study protocols were approved by the Institutional Committee of Laboratory Animal Experimentation of the Research Institute for Microbial Diseases, Osaka University (R02-08-0). All efforts were made during the study to minimize animal suffering and to reduce the number of animals used in the experiments.Ethical approval for the human study protocols was obtained from the ethical committees of Tokyo Medical and Dental University (G2020-034). All subjects signed a consent form approved by the ethical committees of Tokyo Medical and Dental University.