Epithelial response to IFN‐γ promotes SARS‐CoV‐2 infection. Issue 4 (3rd March 2021) - Heuberger, Julian
Abstract: 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. Synopsis: Immune responses to SARS‐CoV‐2 are inefficient in a subset of patients. Here, we used human colonic organoids to ask how IFN‐γ, a central antiviral mediator, affects epithelial differentiation and infection with SARS‐CoV‐2. We find that IFN‐γ promotes cellular differentiation into ACE2‐expressing enterocytes, enabling efficient infection and high virus replication. IFN‐γ is a strong driver of cellular differentiation towards the enterocyte lineage. SARS‐CoV‐2 efficiently infects enterocytes, and IFN‐γ renders organoids susceptible to infection. Targeting immune‐driven epithelial differentiation may serve as a therapeutic strategy. Abstract : Immune responses to SARS‐CoV‐2 are inefficient in a subset of patients. Here, we used human colonic organoids to ask how IFN‐γ, a central antiviral mediator, affects epithelial differentiation and infection with SARS‐CoV‐2. We find that IFN‐γ promotes cellular differentiation into ACE2‐expressing enterocytes, enabling efficient infection and high virus replication.