title: Elucidating the role of the complement control protein in monkeypox pathogenicity.
abstract: Monkeypox virus (MPXV) causes a smallpox-like disease in humans. Clinical and epidemiological studies provide evidence of pathogenicity differences between two geographically distinct monkeypox virus clades: the West African and Congo Basin. Genomic analysis of strains from both clades identified a ∼10 kbp deletion in the less virulent West African isolates sequenced to date. One absent open reading frame encodes the monkeypox virus homologue of the complement control protein (CCP). This modulatory protein prevents the initiation of both the classical and alternative pathways of complement activation. In monkeypox virus, CCP, also known as MOPICE, is a ∼24 kDa secretory protein with sequence homology to this superfamily of proteins. Here we investigate CCP expression and its role in monkeypox virulence and pathogenesis. CCP was incorporated into the West African strain and removed from the Congo Basin strain by homologous recombination. CCP expression phenotypes were confirmed for both wild type and recombinant monkeypox viruses and CCP activity was confirmed using a C4b binding assay. To characterize the disease, prairie dogs were intranasally infected and disease progression was monitored for 30 days. Removal of CCP from the Congo Basin strain reduced monkeypox disease morbidity and mortality, but did not significantly decrease viral load. The inclusion of CCP in the West African strain produced changes in disease manifestation, but had no apparent effect on disease-associated mortality. This study identifies CCP as an important immuno-modulatory protein in monkeypox pathogenesis but not solely responsible for the increased virulence seen within the Congo Basin clade of monkeypox virus.
authors.affiliation: Poxvirus and Rabies Branch, Division of High Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases and Biotechnology Core Facility Branch, Division of Safety Research, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America. fst6@cdc.gov
authors.forename: Paul N
authors.initials: PN
authors.lastname: Hudson
authors.forename: Joshua
authors.initials: J
authors.lastname: Self
authors.forename: Sonja
authors.initials: S
authors.lastname: Weiss
authors.forename: Zachary
authors.initials: Z
authors.lastname: Braden
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Girgis
authors.forename: Ginny
authors.initials: G
authors.lastname: Emerson
authors.forename: Christine
authors.initials: C
authors.lastname: Hughes
authors.forename: Scott A
authors.initials: SA
authors.lastname: Sammons
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Isaacs
authors.forename: Inger K
authors.initials: IK
authors.lastname: Damon
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Olson
mesh_terms: D000818:Animals; D001483:Base Sequence; D003167:Complement Activation; D050716:Complement C4b-Binding Protein / Q000276:immunology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D008297:Male; D008969:Molecular Sequence Data; D045908:Mpox, Monkeypox / Q000276:immunology* / Q000821:virology*; D008993:Monkeypox virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D016366:Open Reading Frames / Q000235:genetics; D011995:Recombination, Genetic; D012589:Sciuridae; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D050716:Complement C4b-Binding Protein; D014764:Viral Proteins