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

SARS-CoV-2, the agent causing 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. However, severe cases of COVID-19 are characterized by an inefficient immune response that fails to clear infection. Using primary epithelial organoids from the colon, we explored how IFN-γ, a central antiviral mediator elevated in COVID-19, affects differentiation, ACE2 expression, and infectivity with SARS-CoV-2. ACE2 is mainly expressed by surface enterocytes of mouse and human colon. 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. Similarly, IFN-γ promoted expression of ACE2 in human primary lung cells. IFN-y driven differentiation increased susceptibility to SARS-CoV-2 infection and electron microscopy revealed that the virus can efficiently complete its full life cycle in IFN-γ-treated enterocytes. Furthermore, infection-induced epithelial interferon signaling promoted enterocyte maturation and enhanced ACE2 expression. We reveal a mechanism by which IFN-y-driven inflammatory responses may increase susceptibility to SARS-CoV-2 and promote its replication. Microarray experiments were performed as dual-color hybridizations on custom whole genome human 8 × 60K multipack microarrays (Agilent-048908). To compensate for dye-specific effects, a dye-reversal color-swap was applied.