title: 25-Hydroxycholesterol Inhibition of Lassa Virus Infection through Aberrant GP1 Glycosylation.
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.
  
  
  
  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.
authors.affiliation: Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Punya
authors.initials: P
authors.lastname: Shrivastava-Ranjan
authors.affiliation: Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Éric
authors.identifier: 0000-0003-3398-8628
authors.initials: É
authors.lastname: Bergeron
authors.affiliation: Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Ayan K
authors.initials: AK
authors.lastname: Chakrabarti
authors.affiliation: Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: César G
authors.initials: CG
authors.lastname: Albariño
authors.affiliation: Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Flint
authors.affiliation: Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Stuart T
authors.initials: ST
authors.lastname: Nichol
authors.affiliation: Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA ccs8@cdc.gov.
authors.forename: Christina F
authors.initials: CF
authors.lastname: Spiropoulou
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D007836:Lassa virus / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D034741:RNA, Small Interfering; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D014759:Viral Envelope Proteins; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D006888:Hydroxycholesterols; D034741:RNA, Small Interfering; D014759:Viral Envelope Proteins; C066508:glycoprotein gp1, lassa virus; C007997:25-hydroxycholesterol; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase