Browsing by Author "Griffiths, William J."

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    Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion
    (NAS, 2020-12) Zang, Ruochen; Case, James Brett; Yutuc, Eylan; Ma, Xiucui; Shen, Sheng; Gomez Castro, Maria Florencia; Liu, Zhuoming; Zeng, Qiru; Zhao, Haiyan; Son, Juhee; Rothlauf, Paul W.; Kreutzberger, Alex J. B.; Hou, Gaopeng; Zhang, Hu; Bose, Sayantan; Wang, Xin; Vahey, Michael D.; Mani, Kartik; Griffiths, William J.; Kirchhausen, Tom; Fremont, Daved H.; Guo, Haitao; Diwan, Abhinav; Wang, Yuqin; Diamond, Michael S.; Whelan, Sean P. J.; Ding, Siyuan; Microbiology and Immunology, School of Medicine
    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.
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    Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
    (Cell Press, 2020-11-17) Baloni, Priyanka; Funk, Cory C.; Yan, Jingwen; Yurkovich, James T.; Kueider-Paisley, Alexandra; Nho, Kwangsik; Heinken, Almut; Jia, Wei; Mahmoudiandehkordi, Siamak; Louie, Gregory; Saykin, Andrew J.; Arnold, Matthias; Kastenmüller, Gabi; Griffiths, William J.; Thiele, Ines; Kaddurah-Daouk, Rima; Price, Nathan D.; Radiology and Imaging Sciences, School of Medicine
    Increasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals supports these results. Our metabolic network analysis suggests that taurine transport, bile acid synthesis, and cholesterol metabolism differ in AD and cognitively normal individuals. We also identify putative transcription factors regulating metabolic genes and influencing altered metabolism in AD. Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain. These findings motivate further research into bile acid metabolism in AD to elucidate their possible connection to cognitive decline.