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Cited by 67Viral Infections and VectorsViral Infections and Outbreaks ResearchVirology and Viral Diseases

25-Hydroxycholesterol Inhibition of Lassa Virus Infection through Aberrant GP1 Glycosylation

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Shrivastava-Ranjan, Punya, Bergeron, Éric, Chakrabarti, Ayan K., Albariño, César G., Flint, Mike, Nichol, Stuart T., Spiropoulou, Christina F.·2016·mBio
DOI 10.1128/mbio.01808-16PMC PMC5181775
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Abstract

Lassa virus (LASV) infection is a major public health concern due to high fatality rates and limited effective treatment. The interferon-stimulated gene cholesterol 25-hydroxylase ( CH25H ) encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC). 25HC is involved in regulating cholesterol biosynthesis and has recently been identified as a potent antiviral targeting enveloped virus entry. Here, we show a previously unrecognized role of CH25H in inhibiting LASV glycoprotein glycosylation and the production of infectious virus. Overexpression of CH25H or treatment with 25HC decreased LASV G1 glycoprotein N -glycan maturation and reduced the production of infectious LASV. Depletion of endogenous CH25H using small interfering RNA (siRNA) enhanced the levels of fully glycosylated G1 and increased infectious LASV production. Finally, LASV particles produced from 25HC-treated cells were found to be less infectious, to incorporate aberrantly glycosylated GP1 species, and to be defective in binding alpha-dystroglycan, an attachment and entry receptor. Our findings identify a novel role for CH25H in controlling LASV propagation and indicate that manipulation of the expression of CH25H or the administration of 25HC may be a useful anti-LASV therapy. IMPORTANCE Lassa fever is an acute viral hemorrhagic fever in humans caused by Lassa virus (LASV). No vaccine for LASV is currently available. Treatment is limited to the administration of ribavirin, which is only effective when given early in the course of illness. Cholesterol 25-hydroxylase ( CH25H ) is a recently identified interferon-stimulated gene (ISG); it encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC), which inhibits several viruses. Here, we identify a novel antiviral mechanism of 25HC that is dependent on inhibiting the glycosylation of Lassa virus (LASV) glycoprotein and reducing the infectivity of LASV as a means of suppressing viral replication. Since N-linked glycosylation is a critical feature of other enveloped-virus glycoproteins, 25HC may be a broad inhibitor of virus infectivity.

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  • 25-hydroxycholesterol confers broad antiviral activity by blocking entry, replication and production of infectious viruses of diverse enveloped viruses.

    “Previous reports have demonstrated that the natural cholesterol metabolite 25-hydroxycholesterol (25-HC), an immune modulator secreted by macrophages during the host response, confers broad antiviral activity by blocking entry, replication and production of infectious viruses of diverse enveloped viruses39–42”

    From Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response (2022) · cites this paper as [41]

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Authors
Shrivastava-Ranjan, P., Bergeron, É., Chakrabarti, A. K., Albariño, C. G., Flint, M., Nichol, S. T., & Spiropoulou, C. F.
Affiliations
Centers for Disease Control and Prevention (US)
Corresponding author
Spiropoulou, Christina F.
ORCID
Venue
mBio
Publisher
American Society for Microbiology
Published
2016-12-30
Volume
7
Issue
6
ISSN
  • 2150-7511 (ISSN-L)
  • 2161-2129
DOI
10.1128/mbio.01808-16
PMC
PMC5181775
OpenAlex
W2566579202
Cited by
67
References
0
Citations by year
2026: 3 · 2025: 5 · 2024: 4 · 2023: 9 · 2022: 10 · 2021: 5 · 2020: 9 · 2019: 12 · 2018: 6 · 2017: 4
FWCI
6.77
Type
journal article
Language
en
Open access
Licence
Locations
  • mBio (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Viral Infections and Vectors
  • Health Sciences › Medicine › Infectious Diseases › Viral Infections and Outbreaks Research
  • Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
Keywords
Lassa virus, 25-hydroxycholesterol, cholesterol 25-hydroxylase, N-glycosylation, viral glycosylation, viral infectivity, alpha-dystroglycan, interferon-stimulated genes, antiviral mechanism, Lassa fever, cholesterol biosynthesis
MeSH terms
Animals, Antiviral Agents, Cell Line, Glycosylation, Humans, Hydroxycholesterols, Lassa virus, Steroid Hydroxylases, Viral Envelope Proteins, Virus Replication, RNA, Small Interfering, Virus Internalization

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