title: Disabling complement regulatory activities of vaccinia virus complement control protein reduces vaccinia virus pathogenicity.
abstract: Poxviruses encode a repertoire of immunomodulatory proteins to thwart the host immune system. One among this array is a homolog of the host complement regulatory proteins that is conserved in various poxviruses including vaccinia (VACV) and variola. The vaccinia virus complement control protein (VCP), which inhibits complement by decaying the classical pathway C3-convertase (decay-accelerating activity), and by supporting inactivation of C3b and C4b by serine protease factor I (cofactor activity), was shown to play a role in viral pathogenesis. However, the role its individual complement regulatory activities impart in pathogenesis, have not yet been elucidated. Here, we have generated monoclonal antibodies (mAbs) that block the VCP functions and utilized them to evaluate the relative contribution of complement regulatory activities of VCP in viral pathogenesis by employing a rabbit intradermal model for VACV infection. Targeting VCP by mAbs that inhibited the decay-accelerating activity as well as cofactor activity of VCP or primarily the cofactor activity of VCP, by injecting them at the site of infection, significantly reduced VACV lesion size. This reduction however was not pronounced when VCP was targeted by a mAb that inhibited only the decay-accelerating activity. Further, the reduction in lesion size by mAbs was reversed when host complement was depleted by injecting cobra venom factor. Thus, our results suggest that targeting VCP by antibodies reduces VACV pathogenicity and that principally the cofactor activity of VCP appears to contribute to the virulence.
authors.affiliation: National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune 411007, India.
authors.forename: John
authors.initials: J
authors.lastname: Bernet
authors.forename: Muzammil
authors.initials: M
authors.lastname: Ahmad
authors.forename: Jayati
authors.initials: J
authors.lastname: Mullick
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Panse
authors.forename: Akhilesh K
authors.initials: AK
authors.lastname: Singh
authors.forename: Pradeep B
authors.initials: PB
authors.lastname: Parab
authors.forename: Arvind
authors.initials: A
authors.lastname: Sahu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D003167:Complement Activation; D003165:Complement System Proteins / Q000276:immunology / Q000378:metabolism; D004546:Elapid Venoms / Q000494:pharmacology; D056747:Immunomodulation; D011817:Rabbits; D014616:Vaccinia virus / Q000276:immunology / Q000472:pathogenicity*; D014764:Viral Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D004546:Elapid Venoms; D014764:Viral Proteins; C016310:cobra venom factor; C066459:complement-control protein, Vaccinia virus; D003165:Complement System Proteins