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.

Syncytia formation by SARS‐CoV‐2‐infected cells

“…IFITMs inhibit SARS‐CoV, 229E, and MERS‐CoV entry, but promote infection by HCoV‐OC43, a coronavirus that causes the common cold (Huang et al , 2011; Bertram et al , 2013; Warren et al , 2014; Wrensch et al , 2014; Zhao et al , 2014; Zhao et al , 2018). IFITMs, as well as other ISGs, including LY6E and Cholesterol 25‐hydrolase (CH25H), impair SARS‐CoV‐2 replication by blocking the fusion of virions (Pfaender et al , 2020; preprint: Zang et al , 2020; Zhao et al , 2020). Most of the experiments regarding these ISGs have been performed with single‐cycle viral pseudotypes.…”

Diabetes, obesity, metabolism, and SARS-CoV-2 infection: the end of the beginning

“…Viral entry was inhibited by 25HC in lung epithelial cells and organoids, via mechanisms requiring activation of acyl-CoA:cholesterol acyltransferase (ACAT), thereby promoting cholesterol transport from the cell membrane to the endoplasmic reticulum ( Wang et al., 2020c ). Consistent with these findings, Zang and colleagues used gain- and loss-of-function experiments to demonstrate key roles for interferon-stimulated CH25H and 25HC in the inhibition of viral membrane fusion and SARS-CoV-2 replication ( Zang et al., 2020 ).…”

Functional interrogation of a SARS-CoV-2 host protein interactome identifies unique and shared coronavirus host factors

“…Consistent with this possibility, one study showed that 27-hydroxycholesterol (27OHC) exerted SARS-CoV-2 antiviral activity in VeroE6 cells at 10 μM, and that overall oxysterols were lower in patients with moderate and severe COVID-19 symptoms than in controls ( Marcello et al., 2020 ). Another study showed that 25OHC had potent SARS-CoV-2 antiviral activity at similar concentrations ( Zang et al., 2020 ). These findings are in strong agreement with work from multiple groups that has demonstrated that 25OHC is a potent inhibitor of many enveloped viruses ( Liu et al., 2013 ).…”