Interferon-Inducible Cholesterol-25-Hydroxylase Broadly Inhibits Viral Entry by Production of 25-Hydroxycholesterol

Abstract

SUMMARY Interferons (IFN) are essential antiviral cytokines that establish the cellular antiviral state through upregulation of hundreds of interferon-stimulated genes (ISGs), most of which have uncharacterized functions and mechanisms. We identified Cholesterol-25-hydroxylase (Ch25h) as an antiviral ISG that can convert cholesterol to a soluble antiviral factor, 25-hydroxycholesterol (25HC). Ch25h expression or 25HC treatment in cultured cells broadly inhibits enveloped viruses including VSV, HSV, HIV, and MHV68 as well as acutely pathogenic EBOV, RVFV, RSSEV, and Nipah viruses under BSL4 conditions. As a soluble oxysterol, 25HC inhibits viral entry by blocking membrane fusion between virus and cell. In animal models, Ch25h-knockout mice were more susceptible to MHV68 lytic infection. Moreover, administration of 25HC in humanized mice suppressed HIV replication and rescued T-cell depletion. Thus, our studies demonstrate a unique mechanism by which IFN achieves its antiviral state through the production of a natural oxysterol to inhibit viral entry and implicate membrane-modifying oxysterols as potential antiviral therapeutics.

25-Hydroxycholesterol Activates the Integrated Stress Response to Reprogram Transcription and Translation in Macrophages

“…Although two recent independent studies demonstrated the broad antiviral activity of 25OHC, the mechanism by which 25OHC suppresses viral infection is still unclear (11,12,59). We demonstrate that 25OHC significantly alters important plasma membrane lipid species and activates the ISR, both of which may contribute to the antiviral activity of 25OHC.…”

“…Experiments described by Liu et al (12) suggest that inhibition of viral entry is a major mechanism by which 25OHC suppresses viral infection. Our lipidomic analysis demonstrated large increases in cholesterol esters consistent with significant recycling of membrane cholesterol to the ER and decreases in sphingomyelin.…”

“…MCMV Infection Stimulates 25OHC Production and Induces Stress Response Gene Transcription-Ch25h is an interferonstimulated gene, and two recent independent publications demonstrated that CH25H and its product 25OHC have broad antiviral activity (11,12). To determine whether the concentrations of 25OHC produced during viral infections were capable of inducing ISR genes, we infected BMDMs with MCMV.…”

“…Mice lacking Ch25h exhibit abnormal immunoglobulin A production by B lymphocytes (6) and dysfunctional B cell migration within follicles (10). Recent studies demonstrated a broad and potent antiviral activity of CH25H and 25OHC (11,12) and suggested that 25OHC impedes viral infection at multiple stages.…”

Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

“…Upon recognizing viral components, host innate immune cells are activated to produce type I interferon (IFN) and proinflammatory cytokines, which are important for elimination of the invading pathogens [1,2]. In particular, the inducible production of type I IFN plays pivotal roles in antiviral immune responses because an appropriate amount of type I IFN induces cellular resistance to viral infection and triggers apoptosis of virus-infected cells [3].…”