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

  1. Ruochen Zang
  2. James Brett Case
  3. Maria Florencia Gomez Castro
  4. Zhuoming Liu
  5. Qiru Zeng
  6. Haiyan Zhao
  7. Juhee Son
  8. Paul W. Rothlauf
  9. Gaopeng Hou
  10. Sayantan Bose
  11. Xin Wang
  12. Michael D. Vahey
  13. Tomas Kirchhausen
  14. Daved H. Fremont
  15. Michael S. Diamond
  16. Sean P.J. Whelan
  17. Siyuan Ding
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Abstract

Cholesterol 25-hydroxylase (CH25H) is an interferon-stimulated gene (ISG) that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an ISG screen against VSV-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of virus replication. Mechanistically, internalized 25HC accumulates in the late endosomes and blocks cholesterol export, thereby restricting SARS-CoV-2 spike protein catalyzed membrane fusion. Our results highlight a unique antiviral mechanism of 25HC and provide the molecular basis for its possible therapeutic development.

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