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. Epub 2020 Oct 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Antiviral Agents
  • Cholesterol
  • Steroid Hydroxylases
  • cholesterol 25-hydroxylase
  • Acetyl-CoA C-Acetyltransferase

Supplementary concepts

  • COVID-19 drug treatment