title: The highly virulent variola and monkeypox viruses express secreted inhibitors of type I interferon.
abstract: Variola virus (VARV) caused smallpox, one of the most devastating human diseases and the first to be eradicated, but its deliberate release represents a dangerous threat. Virulent orthopoxviruses infecting humans, such as monkeypox virus (MPXV), could fill the niche left by smallpox eradication and the cessation of vaccination. However, immunomodulatory activities and virulence determinants of VARV and MPXV remain largely unexplored. We report the molecular characterization of the VARV- and MPXV-secreted type I interferon-binding proteins, which interact with the cell surface after secretion and prevent type I interferon responses. The proteins expressed in the baculovirus system have been purified, and their interferon-binding properties characterized by surface plasmon resonance. The ability of these proteins to inhibit a broad range of interferons was investigated to identify potential adaptation to the human immune system. Furthermore, we demonstrate by Western blot and activity assays the expression of the type I interferon inhibitor during VARV and MPXV infections. These findings are relevant for the design of new vaccines and therapeutics to smallpox and emergent virulent orthopoxviruses because the type I interferon-binding protein is a major virulence factor in animal models, vaccination with this protein induces protective immunity, and its neutralization prevents disease progression.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid), C/Nicolás Cabrera, 1. Campus de Cantoblanco, 28049 Madrid, Spain.
authors.forename: María del Mar
authors.initials: Mdel M
authors.lastname: Fernández de Marco
authors.forename: Alí
authors.initials: A
authors.lastname: Alejo
authors.forename: Paul
authors.initials: P
authors.lastname: Hudson
authors.forename: Inger K
authors.initials: IK
authors.lastname: Damon
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcami
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D056747:Immunomodulation; D007370:Interferon Type I / Q000037:antagonists & inhibitors*; D045908:Mpox, Monkeypox / Q000276:immunology*; D008993:Monkeypox virus / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity; D012899:Smallpox / Q000276:immunology*; D012901:Variola virus / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity; D014764:Viral Proteins / Q000378:metabolism*; D014765:Viral Vaccines / Q000276:immunology; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D007370:Interferon Type I; D014764:Viral Proteins; D014765:Viral Vaccines; D037521:Virulence Factors