title: A novel factor I activity in Nipah virus inhibits human complement pathways through cleavage of C3b.
abstract: Complement is an innate immune system that most animal viruses must face during natural infections. Given that replication and dissemination of the highly pathogenic Nipah virus (NiV) include exposure to environments rich in complement factors, we tested the in vitro sensitivity of NiV to complement-mediated neutralization. Here we show that NiV was completely resistant to in vitro neutralization by normal human serum (NHS). Treatment of purified NiV with NHS activated complement pathways, but there was very little C3 deposition on virus particles. In in vitro reconstitution experiments, NiV particles provided time- and dose-dependent factor I-like protease activity capable of cleaving C3b into inactive C3b (iC3b). NiV-dependent inactivation of C3b only occurred with the cofactors factor H and soluble CR1 but not with CD46. Purified NiV particles did not support C4b cleavage. Electron microscopy of purified NiV particles showed immunogold labeling with anti-factor I antibodies. Our results suggest a novel mechanism by which NiV evades the human complement system through a unique factor I-like activity.
  
  
  OBJECTIVE
  Viruses have evolved mechanisms to limit complement-mediated neutralization, some of which involve hijacking cellular proteins involved in control of inappropriate complement activation. Here we report a previously unknown mechanism whereby NiV provides a novel protease activity capable of in vitro cleavage and inactivation of C3b, a key component of the complement cascade. These data help to explain how an enveloped virus such as NiV can infect and disseminate through body fluids that are rich in complement activity. Disruption of the ability of NiV to recruit complement inhibitors could form the basis for the development of effective therapies and safer vaccines to combat these highly pathogenic emerging viruses.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Johnson
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Borisevich
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Rockx
authors.affiliation: Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA Griffith.Parks@ucf.edu.
authors.forename: Griffith D
authors.initials: GD
authors.lastname: Parks
mesh_terms: D003179:Complement C3b / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017242:Complement Factor H / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D057131:Immune Evasion; D016253:Microscopy, Immunoelectron; D009500:Neutralization Tests; D045405:Nipah Virus / Q000502:physiology*; D017463:Receptors, Complement 3b / Q000378:metabolism; D015678:Viral Structural Proteins / Q000378:metabolism*
chemical_list: C509991:CR1 protein, human; D017463:Receptors, Complement 3b; D015678:Viral Structural Proteins; D003179:Complement C3b; D017242:Complement Factor H; D005340:Fibrinogen