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Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion

Ruochen Zang1,2, James Brett Case3, Eylan Yutuc4

  • 1Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.

Proceedings of the National Academy of Sciences of the United States of America
|November 26, 2020
PubMed

Insights

Cholesterol 25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25HC) effectively inhibit SARS-CoV-2 replication. This discovery offers a potential therapeutic strategy by targeting viral entry mechanisms.

Area of Science:

  • Virology
  • Immunology
  • Biochemistry

Background:

  • Cholesterol 25-hydroxylase (CH25H) is an interferon-stimulated gene with known broad-spectrum antiviral properties against enveloped viruses.
  • SARS-CoV-2, the virus responsible for COVID-19, poses a significant global health challenge, necessitating the identification of novel antiviral targets and therapeutics.

Purpose of the Study:

  • To identify interferon-stimulated genes that inhibit SARS-CoV-2 replication.
  • To investigate the antiviral mechanism of CH25H and its product, 25-hydroxycholesterol (25HC), against SARS-CoV-2.

Main Methods:

  • Conducted an interferon-stimulated gene screen using vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses.
  • Analyzed the accumulation and localization of internalized 25HC within host cells.
  • Investigated the effect of 25HC on SARS-CoV-2 spike protein-mediated membrane fusion.

Main Results:

  • CH25H and 25HC were identified as potent inhibitors of SARS-CoV-2 replication.
  • Internalized 25HC accumulates in late endosomes.
  • 25HC potentially restricts viral entry by blocking cholesterol export, thereby inhibiting SARS-CoV-2 spike protein-mediated membrane fusion.

Conclusions:

  • CH25H and its product 25HC represent promising therapeutic candidates against SARS-CoV-2.
  • The findings elucidate a potential antiviral mechanism of 25HC involving the disruption of host cell cholesterol homeostasis and viral membrane fusion.
  • This study provides a molecular basis for the therapeutic development of 25HC against SARS-CoV-2 and potentially other enveloped viruses.
Keywords:
COVID-19SARS-CoV-2innate immunityinterferonvirus entry

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