Epithelial response to IFN-γ promotes SARS-CoV-2 infection

EMBO Mol Med. 2021 Apr 9;13(4):e13191. doi: 10.15252/emmm.202013191. Epub 2021 Mar 3.


SARS-CoV-2, the agent that causes COVID-19, invades epithelial cells, including those of the respiratory and gastrointestinal mucosa, using angiotensin-converting enzyme-2 (ACE2) as a receptor. Subsequent inflammation can promote rapid virus clearance, but severe cases of COVID-19 are characterized by an inefficient immune response that fails to clear the infection. Using primary epithelial organoids from human colon, we explored how the central antiviral mediator IFN-γ, which is elevated in COVID-19, affects epithelial cell differentiation, ACE2 expression, and susceptibility to infection with SARS-CoV-2. In mouse and human colon, ACE2 is mainly expressed by surface enterocytes. Inducing enterocyte differentiation in organoid culture resulted in increased ACE2 production. IFN-γ treatment promoted differentiation into mature KRT20+ enterocytes expressing high levels of ACE2, increased susceptibility to SARS-CoV-2 infection, and resulted in enhanced virus production in infected cells. Similarly, infection-induced epithelial interferon signaling promoted enterocyte maturation and enhanced ACE2 expression. We here reveal a mechanism by which IFN-γ-driven inflammatory responses induce a vulnerable epithelial state with robust replication of SARS-CoV-2, which may have an impact on disease outcome and virus transmission.

Keywords: ACE2; SARS-CoV-2; differentiation; interferon; organoids.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • COVID-19 / etiology*
  • COVID-19 / immunology
  • COVID-19 / pathology
  • Cell Differentiation / immunology
  • Colon / immunology
  • Colon / pathology
  • Colon / virology
  • Disease Susceptibility
  • Enterocytes / metabolism
  • Enterocytes / pathology
  • Enterocytes / virology
  • Gene Expression
  • Host Microbial Interactions / immunology
  • Humans
  • Interferon-gamma / administration & dosage
  • Interferon-gamma / immunology*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / pathology
  • Intestinal Mucosa / virology
  • Mice
  • Models, Immunological*
  • Organoids / immunology
  • Organoids / pathology
  • Organoids / virology
  • SARS-CoV-2* / genetics
  • SARS-CoV-2* / immunology
  • SARS-CoV-2* / pathogenicity
  • Virus Replication / immunology


  • Interferon-gamma
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2