title: Antibody inhibition of a viral type 1 interferon decoy receptor cures a viral disease by restoring interferon signaling in the liver.
abstract: Type 1 interferons (T1-IFNs) play a major role in antiviral defense, but when or how they protect during infections that spread through the lympho-hematogenous route is not known. Orthopoxviruses, including those that produce smallpox and mousepox, spread lympho-hematogenously. They also encode a decoy receptor for T1-IFN, the T1-IFN binding protein (T1-IFNbp), which is essential for virulence. We demonstrate that during mousepox, T1-IFNs protect the liver locally rather than systemically, and that the T1-IFNbp attaches to uninfected cells surrounding infected foci in the liver and the spleen to impair their ability to receive T1-IFN signaling, thus facilitating virus spread. Remarkably, this process can be reversed and mousepox cured late in infection by treating with antibodies that block the biological function of the T1-IFNbp. Thus, our findings provide insights on how T1-IFNs function and are evaded during a viral infection in vivo, and unveil a novel mechanism for antibody-mediated antiviral therapy.
authors.affiliation: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ren-Huan
authors.initials: RH
authors.lastname: Xu
authors.forename: Daniel
authors.initials: D
authors.lastname: Rubio
authors.forename: Felicia
authors.initials: F
authors.lastname: Roscoe
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Krouse
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Truckenmiller
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Norbury
authors.forename: Paul N
authors.initials: PN
authors.lastname: Hudson
authors.forename: Inger K
authors.initials: IK
authors.lastname: Damon
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcamí
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Sigal
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D004481:Ectromelia virus / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D004482:Ectromelia, Infectious / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D005260:Female; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000821:virology; D012901:Variola virus / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D053585:Virus Attachment / Q000187:drug effects
chemical_list: D000914:Antibodies, Viral; D014764:Viral Proteins; D037521:Virulence Factors; D053633:Receptor, Interferon alpha-beta