Meningococcal factor H binding protein fHbpd184 polymorphism influences clinical course of meningococcal meningitis

• Published in: PloS one 2012-10, Vol.7 (10), p.e47973
• Main Authors: Piet, Jurgen R, Brouwer, Matthijs C, Exley, Rachel, van der Veen, Stijn, van de Beek, Diederik, van der Ende, Arie
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Adults; Amino Acid Substitution; Amino acids; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Antigens, Bacterial - metabolism; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Bacterial Proteins - metabolism; Binding; Binding proteins; Binding, Competitive - immunology; Biology; Bonding; Child; Cohort Studies; Complement factor H; Complement Factor H - genetics; Complement Factor H - immunology; Complement Factor H - metabolism; Complement system; DNA Barcoding, Taxonomic; Forming; Gene polymorphism; Genetic aspects; Genomes; Health aspects; Host-Pathogen Interactions - immunology; Humans; Hydrogen; Hydrogen bonding; Hydrogen bonds; Hydrogen ion concentration; Infections; Kinetics; Lipoproteins; Medical prognosis; Medicine; Meningitis; Meningitis, Meningococcal - immunology; Meningitis, Meningococcal - microbiology; Meningitis, Meningococcal - pathology; Meningococcal disease; Meningococcal meningitis; Microbiology; Middle Aged; Neisseria meningitidis; Neisseria meningitidis - classification; Neisseria meningitidis - genetics; Neisseria meningitidis - immunology; Neurology; Patient outcomes; Patients; Polymorphism; Polymorphism, Genetic; Protein Binding - immunology; Proteins; Recombinant Proteins - immunology; Recombinant Proteins - metabolism; Risk factors; Salts; Septic shock; Severity of Illness Index; Shock, Septic - immunology; Shock, Septic - metabolism; Shock, Septic - microbiology; Surface Plasmon Resonance; Vaccination; Vaccines; Virulence; Virulence factors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0047973

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.