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 (<xref ref-type="bibr" rid="bib4">Davila et al., 2010</xref>). 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 (<xref ref-type="bibr" rid="bib25">Schneider et al., 2006</xref>; <xref ref-type="bibr" rid="bib17">Madico et al., 2007</xref>; <xref ref-type="bibr" rid="bib27">Schneider et al., 2009</xref>). 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.