2. Academic Validation
  3. Cholesterol 25-Hydroxylase inhibits SARS-CoV-2 and other coronaviruses by depleting membrane cholesterol

Cholesterol 25-Hydroxylase inhibits SARS-CoV-2 and other coronaviruses by depleting membrane cholesterol

  • EMBO J. 2020 Nov 2;39(21):e106057. doi: 10.15252/embj.2020106057.
Shaobo Wang # 1,  Wanyu Li # 1 2,  Hui Hui 1 2 3,  Shashi Kant Tiwari 1,  Qiong Zhang 1,  Ben A Croker 4,  Stephen Rawlings 5,  Davey Smith 5,  Aaron F Carlin 5,  Tariq M Rana 1
Affiliations

Affiliations

  • 1 Division of Genetics, Department of Pediatrics, Institute for Genomic Medicine, Program in Immunology, University of California San Diego, La Jolla, CA, USA.
  • 2 Department of Biology, University of California San Diego, La Jolla, CA, USA.
  • 3 Bioinformatics Program, University of California San Diego, La Jolla, CA, USA.
  • 4 Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
  • 5 Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • # Contributed equally.
PMID: 32944968 DOI: 10.15252/embj.2020106057
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 (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.

Keywords

COVID-19 treatment; cholesterol 25-hydroxylase; innate immunity; restriction factor of coronaviruses; viral fusion.

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