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.


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


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