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

  • Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):32105-32113. doi: 10.1073/pnas.2012197117.
Ruochen Zang  1  2 ,  James Brett Case  3 ,  Eylan Yutuc  4 ,  Xiucui Ma  5  6 ,  Sheng Shen  7 ,  Maria Florencia Gomez Castro  1 ,  Zhuoming Liu  1 ,  Qiru Zeng  1 ,  Haiyan Zhao  8 ,  Juhee Son  1  9 ,  Paul W Rothlauf  1  10 ,  Alex J B Kreutzberger  11  12 ,  Gaopeng Hou  1 ,  Hu Zhang  7 ,  Sayantan Bose  13 ,  Xin Wang  2 ,  Michael D Vahey  14 ,  Kartik Mani  5  6 ,  William J Griffiths  4 ,  Tom Kirchhausen  11  12 ,  Daved H Fremont  8 ,  Haitao Guo  7 ,  Abhinav Diwan  5  6 ,  Yuqin Wang  4 ,  Michael S Diamond  1  3  8 ,  Sean P J Whelan  1 ,  Siyuan Ding  15
Affiliations
  • 1. Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
  • 2. Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China, 266100 Qingdao, China.
  • 3. Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
  • 4. Swansea University Medical School, SA2 8PP Swansea, United Kingdom.
  • 5. Center for Cardiovascular Research and Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63111.
  • 6. John Cochran VA Medical Center, St. Louis, MO 63106.
  • 7. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202.
  • 8. Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.
  • 9. Program in Molecular Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.
  • 10. Program in Virology, Harvard Medical School, Boston, MA 02115.
  • 11. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
  • 12. Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
  • 13. Autonomous Therapeutics, Inc., New York, NY 10013.
  • 14. Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO 63110.
  • 15. Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110; [email protected].
PMID: 33239446 DOI: 10.1073/pnas.2012197117
Abstract

Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad Antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of Cholesterol export. Our results highlight one of the possible Antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development.

Keywords
COVID-19; SARS-CoV-2; innate immunity; interferon; virus entry.