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EMBO J ; 39(21): e106057, 2020 11 02.
Article in English | MEDLINE | ID: covidwho-846583


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 (ISGs), cholesterol 25-hydroxylase (CH25H), is induced by SARS-CoV-2 infection in vitro and in COVID-19-infected patients. CH25H converts cholesterol to 25-hydrocholesterol (25HC) and 25HC shows broad anti-coronavirus activity by blocking membrane fusion. Furthermore, 25HC inhibits USA-WA1/2020 SARS-CoV-2 infection in lung epithelial cells and viral entry in human lung organoids. Mechanistically, 25HC 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 25HC through depleting accessible cholesterol on the plasma membrane to suppress virus-cell fusion. Since 25HC 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.

Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Cholesterol/metabolism , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Respiratory Mucosa/virology , Steroid Hydroxylases/pharmacology , Virus Internalization/drug effects , Acetyl-CoA C-Acetyltransferase/metabolism , Animals , COVID-19 , Cell Line , Cell Membrane/drug effects , Cell Membrane/metabolism , Chlorocebus aethiops , Enzyme Activation/drug effects , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Organoids/virology , Pandemics , Respiratory Mucosa/drug effects , SARS Virus/drug effects , SARS-CoV-2 , Vero Cells