title: Meningococcal factor H binding protein fHbpd184 polymorphism influences clinical course of meningococcal meningitis.
abstract: Factor H Binding protein (fHbp) is an important meningococcal virulence factor, enabling the meningococcus to evade the complement system, and a main target for vaccination. Recently, the structure of fHBP complexed with factor H (fH) was published. Two fHbp glutamic acids, E(283) and E(304), form salt bridges with fH, influencing interaction between fHbp and fH. Fifteen amino acids were identified forming hydrogen bonds with fH. We sequenced fHbp of 254 meningococcal isolates from adults with meningococcal meningitis included in a prospective clinical cohort to study the effect of fHbp variants on meningococcal disease severity and outcome. All fHbp of subfamily A had E304 substituted with T304. Of the 15 amino acids in fHbp making hydrogen bonds to fH, 3 were conserved, 11 show a similar distribution between the two fHbp subfamilies as the polymorphism at position 304. The proportion of patients infected with meningococci with fHbp of subfamily A with unfavorable outcome was 2.5-fold lower than that of patients infected with meningococci with fHbp of subfamily B (2 of 40 (5%) vs. 27 of 213 (13%) (P = 0.28). The charge of 2 of 15 amino acids (at position 184 and 306) forming hydrogen bonds was either basic or acidic. The affinity of fHbp(K184) and of fHbp(D184) for recombinant purified human fH was assessed by Surface Plasmon Resonance and showed average K(D) of 2.60×10(-8) and 1.74×10(-8), respectively (ns). Patients infected with meningococci with fHbp(D184) were more likely to develop septic shock during admission (11 of 42 [26%] vs. 19 of 211 [9%]; P = 0.002) resulting in more frequent unfavorable outcome (9 of 42 [21%] vs. 20 of 211 [10%]; P = 0.026). In conclusion, we dentified fHBP(D184) to be associated with septic shock in patients with meningococcal meningitis.
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam-CINIMA, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jurgen R
authors.initials: JR
authors.lastname: Piet
authors.forename: Matthijs C
authors.initials: MC
authors.lastname: Brouwer
authors.forename: Rachel
authors.initials: R
authors.lastname: Exley
authors.forename: Stijn
authors.initials: S
authors.lastname: van der Veen
authors.forename: Diederik
authors.initials: D
authors.lastname: van de Beek
authors.forename: Arie
authors.initials: A
authors.lastname: van der Ende
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001667:Binding, Competitive / Q000276:immunology; D002648:Child; D015331:Cohort Studies; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D058893:DNA Barcoding, Taxonomic; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007700:Kinetics; D008585:Meningitis, Meningococcal / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008875:Middle Aged; D009345:Neisseria meningitidis / Q000145:classification / Q000235:genetics / Q000276:immunology*; D011110:Polymorphism, Genetic; D011485:Protein Binding / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D020349:Surface Plasmon Resonance
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D011994:Recombinant Proteins; C484699:factor H-binding protein, Neisseria meningitidis; D017242:Complement Factor H