@article{f5d2d9bced93437499d5c3452ac1582e,
title = "Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion",
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, Innate immunity, Interferon, SARS-CoV-2, Virus entry",
author = "Ruochen Zang and Case, {James Brett} and Eylan Yutuc and Xiucui Ma and Sheng Shen and Castro, {Maria Florencia Gomez} and Zhuoming Liu and Qiru Zeng and Haiyan Zhao and Juhee Son and Rothlauf, {Paul W.} and Kreutzberger, {Alex J.B.} and Gaopeng Hou and Hu Zhang and Sayantan Bose and Xin Wang and Vahey, {Michael D.} and Kartik Mani and Griffiths, {William J.} and Tom Kirchhausen and Fremont, {Daved H.} and Haitao Guo and Abhinav Diwan and Yuqin Wang and Diamond, {Michael S.} and Whelan, {Sean P.J.} and Siyuan Ding",
note = "Funding Information: We thank Drs. Rohit Pappu (School of Engineering), Anil Cashikar, Steven Paul (Department of Psychiatry), and David Holtzman (Department of Neurology) for helpful discussion; and Matthew Williams (Department of Molecular Microbiology, Media and Glassware Facility), Wandy Betty (Molecular Microbiology Imaging Facility), and Marina Cella and Erica Lantelme (Department of Pathology and Immunology, Flow Cytometry Core Facility) for assistance. The SARS-CoV-2 Taqman probe and viral RNA standards were prepared by Adam Bailey (Department of Medicine, Division of Infectious Diseases). This work is supported by NIH Digestive Diseases Research Core Center Grants P30 DK052574, R00 AI135031, and R01 AI150796 and the COVID-19 Fast Grants Funding (to S.D.), and GM130386 to T.K.; Harvard Virology Program, NIH training Grant T32 AI07245 postdoctoral fellowship (to A.J.B.K.); NIH Contracts and Grants 75N93019C00062 and R01 AI127828 and the Defense Advanced Research Project Agency HR001117S0019 (to M.S.D.); and unrestricted funds from the Washington University School of Medicine in St. Louis and R37 AI059371 (to S.P.J.W.). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship. Work in Swansea University was supported by Biotechnology and Biological Sciences Research Council Grant BB/ L001942/1 (to Y.W.). Funding Information: ACKNOWLEDGMENTS. We thank Drs. Rohit Pappu (School of Engineering), Anil Cashikar, Steven Paul (Department of Psychiatry), and David Holtzman (Department of Neurology) for helpful discussion; and Matthew Williams (Department of Molecular Microbiology, Media and Glassware Facility), Wandy Betty (Molecular Microbiology Imaging Facility), and Marina Cella and Erica Lantelme (Department of Pathology and Immunology, Flow Cytometry Core Facility) for assistance. The SARS-CoV-2 Taqman probe and viral RNA standards were prepared by Adam Bailey (Department of Medicine, Division of Infectious Diseases). This work is supported by NIH Digestive Diseases Research Core Center Grants P30 DK052574, R00 AI135031, and R01 AI150796 and the COVID-19 Fast Grants Funding (to S.D.), and GM130386 to T.K.; Harvard Virology Program, NIH training Grant T32 AI07245 postdoctoral fellowship (to A.J.B.K.); NIH Contracts and Grants 75N93019C00062 and R01 AI127828 and the Defense Advanced Research Project Agency HR001117S0019 (to M.S.D.); and unrestricted funds from the Washington University School of Medicine in St. Louis and R37 AI059371 (to S.P.J.W.). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship. Work in Swansea University was supported by Biotechnology and Biological Sciences Research Council Grant BB/ L001942/1 (to Y.W.). Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = dec,
day = "15",
doi = "10.1073/pnas.2012197117",
language = "English",
volume = "117",
pages = "32105--32113",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "50",
}