title: Competition between antagonistic complement factors for a single protein on N. meningitidis rules disease susceptibility.
abstract: Genome-wide association studies have found variation within the complement factor H gene family links to host susceptibility to meningococcal disease caused by infection with Neisseria meningitidis (Davila et al., 2010). Mechanistic insights have been challenging since variation within this locus is complex and biological roles of the factor H-related proteins, unlike factor H, are incompletely understood. N. meningitidis subverts immune responses by hijacking a host-immune regulator, complement factor H (CFH), to the bacterial surface (Schneider et al., 2006; Madico et al., 2007; Schneider et al., 2009). We demonstrate that complement factor-H related 3 (CFHR3) promotes immune activation by acting as an antagonist of CFH. Conserved sequences between CFH and CFHR3 mean that the bacterium cannot sufficiently distinguish between these two serum proteins to allow it to hijack the regulator alone. The level of protection from complement attack achieved by circulating N. meningitidis therefore depends on the relative levels of CFH and CFHR3 in serum. These data may explain the association between genetic variation in both CFH and CFHR3 and susceptibility to meningococcal disease.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Joseph J E
authors.initials: JJ
authors.lastname: Caesar
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Hayley
authors.initials: H
authors.lastname: Lavender
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Ward
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Exley
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Jack
authors.initials: J
authors.lastname: Eaton
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Chittock
authors.affiliation: Centre for Complement and Inflammation Research, Department of Medicine, Imperial College, London, United Kingdom.
authors.forename: Talat H
authors.initials: TH
authors.lastname: Malik
authors.affiliation: Centre for Complement and Inflammation Research, Department of Medicine, Imperial College, London, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Goiecoechea De Jorge
authors.affiliation: Centre for Complement and Inflammation Research, Department of Medicine, Imperial College, London, United Kingdom.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Tang
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lea
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D001798:Blood Proteins / Q000737:chemistry / Q000235:genetics; D017242:Complement Factor H / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D016920:Meningitis, Bacterial / Q000235:genetics* / Q000276:immunology; D008969:Molecular Sequence Data; D009345:Neisseria meningitidis / Q000378:metabolism* / Q000472:pathogenicity; D017386:Sequence Homology, Amino Acid
chemical_list: D001426:Bacterial Proteins; D001798:Blood Proteins; C105970:CFHR3 protein, human; D017242:Complement Factor H
keywords: Neisseria meningitidis; complement evasion; genetic susceptibility; immunology; infectious disease; microbiology