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

Shaobo Wang1, Wanyu Li1,2, Hui Hui1,2,3

  • 1Division of Genetics, Department of Pediatrics, Institute for Genomic Medicine, Program in Immunology, University of California San Diego, La Jolla, CA, USA.

The EMBO Journal
|September 18, 2020
PubMed

Insights

Cholesterol 25-hydroxylase (CH25H) is induced by SARS-CoV-2 infection. Its product, 25-hydrocholesterol (25HC), inhibits viral entry by blocking membrane fusion, offering a potential therapeutic for COVID-19.

Area of Science:

  • Virology and Immunology
  • Molecular Biology

Background:

  • Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a global pandemic lacking vaccines or antiviral therapies.
  • Understanding SARS-CoV-2 pathogenesis and host immune responses is critical.
  • Related coronaviruses like SARS-CoV and MERS-CoV have caused significant past epidemics.

Purpose of the Study:

  • To investigate the role of interferon-stimulated genes (ISGs) in SARS-CoV-2 infection.
  • To identify potential therapeutic targets for COVID-19 and other emerging viral diseases.

Main Methods:

  • Induction of cholesterol 25-hydroxylase (CH25H) by SARS-CoV-2 in vitro and in patient samples.
  • Assessment of 25-hydrocholesterol (25HC) antiviral activity against SARS-CoV-2 in lung epithelial cells and organoids.
  • Mechanistic studies on how 25HC inhibits viral membrane fusion via ACAT activation and cholesterol depletion.

Main Results:

  • CH25H is induced by SARS-CoV-2 infection.
  • 25HC demonstrates broad anti-coronavirus activity by inhibiting viral membrane fusion.
  • 25HC effectively suppresses SARS-CoV-2 infection and entry in lung cells and organoids.

Conclusions:

  • 25HC inhibits viral entry by depleting accessible cholesterol from the plasma membrane, suppressing virus-cell fusion.
  • 25HC represents a potential therapeutic candidate for COVID-19 and future viral outbreaks due to its broad antiviral mechanism and low toxicity.
Keywords:
COVID-19 treatmentcholesterol 25-hydroxylaseinnate immunityrestriction factor of coronavirusesviral fusion

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