Abstract Coronavirus disease 2019 ( COVID ‐19) is caused by SARS ‐CoV‐2 and has spread across the globe. SARS ‐CoV‐2 is a highly infectious virus with no vaccine or antiviral therapy available to control the pandemic; therefore, it is crucial to understand the mechanisms of viral pathogenesis and the host immune responses to SARS ‐CoV‐2. SARS ‐CoV‐2 is a new member of the betacoronavirus genus like other closely related viruses including SARS ‐CoV and Middle East respiratory syndrome coronavirus ( MERS ‐CoV). Both SARS ‐CoV and MERS ‐CoV have caused serious outbreaks and epidemics in the past eighteen years. Here, we report that one of the interferon‐stimulated genes ( ISG s), cholesterol 25‐hydroxylase ( CH 25H ), is induced by SARS ‐CoV‐2 infection in vitro and in COVID ‐19‐infected patients. CH 25H converts cholesterol to 25‐hydrocholesterol (25 HC ) and 25 HC shows broad anti‐coronavirus activity by blocking membrane fusion. Furthermore, 25 HC inhibits USA ‐ WA 1/2020 SARS ‐CoV‐2 infection in lung epithelial cells and viral entry in human lung organoids. Mechanistically, 25 HC inhibits viral membrane fusion by activating the ER ‐localized acyl‐CoA:cholesterol acyltransferase ( ACAT ) which leads to the depletion of accessible cholesterol from the plasma membrane. Altogether, our results shed light on a potentially broad antiviral mechanism by 25 HC through depleting accessible cholesterol on the plasma membrane to suppress virus–cell fusion. Since 25 HC is a natural product with no known toxicity at effective concentrations, it provides a potential therapeutic candidate for COVID ‐19 and emerging viral diseases in the future. Interferon‐induced cholesterol hydroxylation, and subsequent activation of the ER ‐localized ACAT enzyme that depletes accessible cholesterol, represents a new host defence mechanism restricting membrane fusion and entry of severely pathogenic coronaviruses.
【저자키워드】 Innate immunity, Microbiology, Virology & Host Pathogen Interaction, viral fusion, cholesterol 25‐hydroxylase,