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

Ruochen Zang; James Brett Case; Eylan Yutuc; Xiucui Ma; Sheng Shen; Maria Florencia Gomez Castro; Zhuoming Liu; Qiru Zeng; Haiyan Zhao; Juhee Son; Paul W Rothlauf; Alex J B Kreutzberger; Gaopeng Hou; Hu Zhang; Sayantan Bose; Xin Wang; Michael D Vahey; Kartik Mani; William J Griffiths; Tom Kirchhausen; Daved H Fremont; Haitao Guo; Abhinav Diwan; Yuqin Wang; Michael S Diamond; Sean P J Whelan; Siyuan Ding

doi:10.1073/pnas.2012197117

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. Epub 2020 Nov 25.

Authors

Ruochen Zang^{1

2}, James Brett Case³, Eylan Yutuc⁴, Xiucui Ma^{5

6}, Sheng Shen⁷, Maria Florencia Gomez Castro¹, Zhuoming Liu¹, Qiru Zeng¹, Haiyan Zhao⁸, Juhee Son^{1

9}, Paul W Rothlauf^{1

10}, Alex J B Kreutzberger^{11

12}, Gaopeng Hou¹, Hu Zhang⁷, Sayantan Bose¹³, Xin Wang², Michael D Vahey¹⁴, Kartik Mani^{5

6}, William J Griffiths⁴, Tom Kirchhausen^{11

12}, Daved H Fremont⁸, Haitao Guo⁷, Abhinav Diwan^{5

6}, Yuqin Wang⁴, Michael S Diamond^{1

3

8}, Sean P J Whelan¹, Siyuan Ding¹⁵

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; siyuan.ding@wustl.edu.

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.

Publication types

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

MeSH terms

Antiviral Agents / pharmacology
COVID-19 / metabolism
COVID-19 / pathology
COVID-19 / virology
COVID-19 Drug Treatment*
Endosomes / genetics*
Endosomes / metabolism
Humans
Hydroxycholesterols / pharmacology*
Interferons / metabolism
Membrane Fusion / drug effects
SARS-CoV-2 / drug effects
SARS-CoV-2 / metabolism
SARS-CoV-2 / pathogenicity
Severe acute respiratory syndrome-related coronavirus / drug effects
Severe acute respiratory syndrome-related coronavirus / metabolism
Severe acute respiratory syndrome-related coronavirus / pathogenicity
Spike Glycoprotein, Coronavirus / antagonists & inhibitors*
Spike Glycoprotein, Coronavirus / genetics
Virus Internalization / drug effects
Virus Replication / drug effects

Substances

Antiviral Agents
Hydroxycholesterols
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2
25-hydroxycholesterol
Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding