Inhibition of pathogenic non-enveloped viruses by 25-hydroxycholesterol and 27-hydroxycholesterol

Civra, Andrea; Cagno, Valeria; Donalisio, Manuela; Biasi, Fiorella; Leonarduzzi, Gabriella; Poli, Giuseppe; Lembo, David

doi:10.1038/srep07487

Cited by 95 publications

(100 citation statements)

References 21 publications

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“…25HC has been reported as a potent antiviral mediator against a panel of enveloped and nonenveloped virus (20,21,31,47). However, these studies differ in their conclusions about the exact antiviral mechanism.…”

Section: Discussionmentioning

confidence: 70%

Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection

Tang

Tao

et al. 2015

J Virol

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Hepatitis C virus (HCV), a single-stranded positive-sense RNA virus of the Flaviviridae family, causes chronic liver diseases, including hepatitis, cirrhosis, and cancer. HCV infection is critically dependent on host lipid metabolism, which contributes to all stages of the viral life cycle, including virus entry, replication, assembly, and release. 25-Hydroxycholesterol (25HC) plays a critical role in regulating lipid metabolism, modulating immune responses, and suppressing viral pathogens. In this study, we showed that 25HC and its synthesizing enzyme cholesterol 25-hydroxylase (CH25H) efficiently inhibit HCV infection at a postentry stage. CH25H inhibits HCV infection by suppressing the maturation of SREBPs, critical transcription factors for host lipid biosynthesis. Interestingly, CH25H is upregulated upon poly(I·C) treatment or HCV infection in hepatocytes, which triggers type I and III interferon responses, suggesting that the CH25H induction constitutes a part of host innate immune response. To our surprise, in contrast to studies in mice, CH25H is not induced by interferons in human cells and knockdown of STAT-1 has no effect on the induction of CH25H, suggesting CH25H is not an interferon-stimulated gene in humans but rather represents a primary and direct host response to viral infection. Finally, knockdown of CH25H in human hepatocytes significantly increases HCV infection. In summary, our results demonstrate that CH25H constitutes a primary innate response against HCV infection through regulating host lipid metabolism. Manipulation of CH25H expression and function should provide a new strategy for anti-HCV therapeutics. IMPORTANCERecent studies have expanded the critical roles of oxysterols in regulating immune response and antagonizing viral pathogens. Here, we showed that one of the oxysterols, 25HC and its synthesizing enzyme CH25H efficiently inhibit HCV infection at a postentry stage via suppressing the maturation of transcription factor SREBPs that regulate lipid biosynthesis. Furthermore, we found that CH25H expression is upregulated upon poly(I·C) stimulation or HCV infection, suggesting CH25H induction constitutes a part of host innate immune response. Interestingly, in contrast to studies in mice showing that ch25h is an interferon-stimulated gene, CH25H cannot be induced by interferons in human cells but rather represents a primary and direct host response to viral infection. Our studies demonstrate that the induction of CH25H represents an important host innate response against virus infection and highlight the role of lipid effectors in host antiviral strategy. H epatitis C virus (HCV), a causative agent of acute and chronic liver diseases, is an enveloped positive-sense single-stranded RNA virus belonging to the family of Flaviviridae. Approximately 170 million people worldwide are infected with HCV. The tremendous progress has been achieved in the therapeutics of chronic hepatitis C thanks to the development of direct antiviral agents (DAAs), but the worldwide application of the...

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Section: Discussionmentioning

confidence: 70%

Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection

Tang

Tao

et al. 2015

J Virol

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“…The oxysterol 25HC is a metabolite of cholesterol produced and secreted by macrophages and has multiple effects on lipid metabolism. Recently, 25HC was reported to be a potent antiviral mediator against various kinds of viruses (25,26). In this study, the addition of 25HC drastically inhibited SFTSV growth, particularly the inhibition of virus entry ( Fig.…”

Section: Discussionmentioning

confidence: 84%

Characterization of Glycoprotein-Mediated Entry of Severe Fever with Thrombocytopenia Syndrome Virus

Tani

Shimojima

Fukushi

et al. 2016

J Virol

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Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever with a high case fatality rate caused by SFTS virus (SFTSV). Effective vaccines and specific therapies for SFTS are urgently sought, and investigation into virus-host cell interactions is expected to contribute to the development of antiviral strategies. In this study, we have developed a pseudotype vesicular stomatitis virus (VSV) bearing the unmodified Gn/Gc glycoproteins (GPs) of SFTSV (SFTSVpv). We have analyzed the host cell entry of this pseudotype virus and native SFTSV. Both SFTSVpv and SFTSV exhibited high infectivity in various mammalian cell lines. The use of lysosomotropic agents indicated that virus entry occurred via pH-dependent endocytosis. SFTSVpv and SFTSV infectivity was neutralized by serial dilutions of convalescent-phase patient sera. Entry of SFTSVpv and growth of SFTSV were increased in Raji cells expressing not only the C-type lectin dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) but also DC-SIGN-related (DC-SIGNR) and liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin). 25-Hydroxycholesterol (25HC), a soluble oxysterol metabolite, inhibited the cell entry of SFTSVpv and the membrane fusion of SFTSV. These results indicate that pH-dependent endocytosis of SFTSVpv and SFTSV is enhanced by attachment to certain C-type lectins. SFTSVpv is an appropriate model for the investigation of SFTSV-GP-mediated cell entry and virus neutralization at lower biosafety levels. Furthermore, 25HC may represent a potential antiviral agent against SFTS. IMPORTANCESFTSV is a recently discovered bunyavirus associated with SFTS, a viral hemorrhagic fever with a high case fatality rate endemic to China, South Korea, and Japan. Because little is known about the characteristics of the envelope protein and entry mechanisms of SFTSV, further studies will be required for the development of a vaccine or effective therapies. In this study, we investigated the mechanism of SFTSV cell entry using SFTSVpv and the native virus. SFTSV can grow in nonsusceptible cell lines in the presence of certain C-type lectins. Moreover, 25HC, an oxysterol metabolite, may represent a potential therapeutic inhibitor of SFTSV infection. Severe fever with thrombocytopenia syndrome (SFTS), a newly recognized emerging viral infectious disease, is caused by a novel phlebovirus in the family Bunyaviridae, SFTS virus (SFTSV) (1-3). SFTSV can be transmitted to humans by tick bites, causing abrupt high fever, thrombocytopenia, leukopenia, and gastrointestinal symptoms, with a high case fatality rate (4). SFTSV is a single-stranded negative-sense RNA virus with three genomic segments, L, M, and S. The L segment encodes a viral RNA polymerase, while the M segment encodes the two viral envelope glycoproteins (GPs) Gn and Gc. The S segment is an ambisense RNA encoding a nucleoprotein (NP) and a nonstructural protein (NSs). The Gn and Gc proteins of bunyaviruses are usually localized in the Golgi app...

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“…Both studies confirmed broad antiviral activity of 25HC in vitro against different classes of lipid-enveloped RNA and DNA viruses. This was subsequently reaffirmed by several independent studies (Arita et al 2013;Chen et al 2014;Mboko et al 2014), and the antiviral activity was additionally extended to nonenveloped viruses (Civra et al 2014). Table 1 summarizes the viruses whose susceptibility to 25HC's antiviral effects has been validated.…”

Section: Hc: Broad Antiviral Lipid Effectormentioning

confidence: 57%

Armand-Frappier Outstanding Student Award — The emerging role of 25-hydroxycholesterol in innate immunity

2015

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Abstract:The metabolic interplay between hosts and viruses plays a crucial role in determining the outcome of viral infection. Viruses reorchestrate the host's primary metabolic gene networks, including genes associated with mevalonate and isoprenoid synthesis, to acquire the necessary energy and structural components for their viral life cycles. Recent work has demonstrated that the interferon-mediated antiviral response suppresses the sterol pathway through production of a signalling molecule, 25-hydroxycholesterol (25HC). This oxysterol has been shown to exert multiple effects, both through incorporation into host cellular membranes as well as through transcriptional control. Herein, we summarize our current understanding of the multifunctional roles of 25HC in the mammalian innate antiviral response.Key words: 25-hydroxycholesterol, cholesterol-25-hydroxylase, metabolism, virus, immunity.Résumé : Les interactions métaboliques entre les hôtes et les virus jouent un rôle crucial qui déterminera l'issue de l'infection virale. Les virus réorganisent les réseaux de gènes métaboliques primaires de l'hôte, dont les gènes liés à la synthèse du mévalonate et des isoprénoïdes, afin d'acquérir l'énergie et les éléments structuraux néces-saires à leur cycle de vie. Des travaux récents ont démontré que la réponse antivirale activée par les interférons supprime la voie des stérols par la production d'une molécule de signalisation, le 25-hydroxycholestérol (25HC). On a révélé que cet oxystérol avait plus d'un effet, tant par son intégration dans les membranes de la cellule-hôte que par le contrôle de la transcription. Nous résumons ici notre conception actuelle des rôles multifonctionnels du 25HC dans la réponse antivirale innée chez les mammifères. [Traduit par la Rédaction] -clés : 25-hydroxycholestérol, cholestérol-25-hydroxylase, métabolisme, virus, immunité. Mots

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Inhibition of pathogenic non-enveloped viruses by 25-hydroxycholesterol and 27-hydroxycholesterol

Cited by 95 publications

References 21 publications

Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection

Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection

Characterization of Glycoprotein-Mediated Entry of Severe Fever with Thrombocytopenia Syndrome Virus

Armand-Frappier Outstanding Student Award — The emerging role of 25-hydroxycholesterol in innate immunity

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