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

Julian Heuberger,Rosa Schmuck,Volker Brinkmann,Daria Vladimirova,Frank Tacke,Hans‐Joachim Mollenkopf,Nikolaus Osterrieder,Christian Goosmann,Manqiang Lin,Jakob Trimpert,Michael Sigal

doi:10.15252/emmm.202013191

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.

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease (COVID-19) and has already infected more than 80 million people around the globe
IFN-c is a strong driver of angiotensinconverting enzyme 2 (ACE2) expression in human colon organoids
To explore the potential connection between IFN-c and ACE2, we established cultures of human colon organoids. hCOs grown in full medium showed signs of self-organization and development of crypt-like buds (Fig 1C, left panel)

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease (COVID-19) and has already infected more than 80 million people around the globe. SARS-CoV-2 invades epithelial cells of the mucosal surfaces of the upper and lower respiratory tract as well as the gastrointestinal tract, but can replicate in epithelia of other organs (Zhu et al, 2020). In addition to respiratory symptoms, gastrointestinal symptoms are common in COVID-19 and recent data revealed that the virus can efficiently infect enterocytes (Cholankeril et al, 2020; Lamers et al, 2020). Gastrointestinal symptoms have been linked to prolonged infection and a more severe course of disease (Zhong et al, 2020). The entry receptor for SARS-CoV-2 is angiotensinconverting enzyme 2 (ACE2) expressed on epithelial cells. Spike glycoproteins present in the viral envelope bind to ACE2 and are proteolytically cleaved by the transmembrane protease serine protease 2 (TMPRSS2), which results in virus entry (Hoffmann et al, 2020; Matsuyama et al, 2020; Yan et al, 2020)

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