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Abstract

During an outbreak of invasive meningococcal disease (IMD) at the University of Southampton, UK, in 1997, two serogroup C isolates were retrieved from a student (‘Case’), who died of IMD, and a close contact (‘Carrier’) who, after mouth-to-mouth resuscitation on the deceased, did not contract the disease. Genomic comparison of the isolates demonstrated extensive nucleotide sequence identity, with differences identified in eight genes. Here, comparative proteomics was used to measure differential protein expression between the isolates and investigate whether the differences contributed to the clinical outcomes. A total of six proteins were differentially expressed: four proteins (methylcitrate synthase, PrpC; hypothetical integral membrane protein, Imp; fructose-1,6-bisphosphate aldolase, Fba; aldehyde dehydrogenase A, AldA) were upregulated in the Case isolate, while one protein (Type IV pilus-associated protein, PilC2) was downregulated. Peptides for factor H binding protein (fHbp), a major virulence factor and antigenic protein, were only detected in the Case, with a single base deletion (ΔT366) in the Carrier fHbp causing lack of its expression. Expression of fHbp resulted in an increased resistance of the Case isolate to complement-mediated killing in serum. Complementation of fHbp expression in the Carrier increased its serum resistance by approximately 8-fold. Moreover, a higher serum bactericidal antibody titre was seen for the Case isolate when using sera from mice immunized with Bexsero (GlaxoSmithKline), a vaccine containing fHbp as an antigenic component. This study highlights the role of fHbp in the differential complement resistance of the Case and the Carrier isolates. Expression of fHbp in the Case resulted in its increased survival in serum, possibly leading to active proliferation of the bacteria in blood and death of the student through IMD. Moreover, enhanced killing of the Case isolate by sera raised against an fHbp-containing vaccine, Bexsero, underlines the role and importance of fHbp in infection and immunity.

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2021-09-09
2024-12-07
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References

  1. Read RC. Neisseria meningitidis; clones, carriage, and disease. Clin Microbiol Infect 2014; 20:391–395 [View Article]
    [Google Scholar]
  2. Claus H, Maiden MC, Wilson DJ, McCarthy ND, Jolley KA et al. Genetic analysis of meningococci carried by children and young adults. J Infect Dis 2005; 191:1263–1271 [View Article]
    [Google Scholar]
  3. Cartwright KA, Stuart JM, Jones DM, Noah ND. The Stonehouse survey: nasopharyngeal carriage of meningococci and Neisseria lactamica. Epidemiol Infect 1987; 99:591–601 [View Article]
    [Google Scholar]
  4. Stephens DS. Uncloaking the meningococcus: dynamics of carriage and disease. The Lancet 1999; 353:941–942 [View Article]
    [Google Scholar]
  5. Gabutti G, Stefanati A, Kuhdari P. Epidemiology of Neisseria meningitidis infections: case distribution by age and relevance of carriage. J Prev Med Hyg 2015; 56:E116–20 [PubMed]
    [Google Scholar]
  6. Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. Vaccine 2009; 27 Suppl 2:B51–63 [View Article]
    [Google Scholar]
  7. Pelton SI. The Global evolution of Meningococcal epidemiology following the introduction of Meningococcal vaccines. J Adolesc Health 2016; 59:S3–S11 [View Article]
    [Google Scholar]
  8. Ala’aldeen DA, Oldfield NJ, Bidmos FA, Abouseada NM, Ahmed NW et al. Carriage of meningococci by university students, United Kingdom. Emerg Infect Dis 2011; 17:1762–1763 [View Article]
    [Google Scholar]
  9. Russell JE, Urwin R, Gray SJ, Fox AJ, Feavers IM et al. Molecular epidemiology of meningococcal disease in England and Wales 1975-1995, before the introduction of serogroup C conjugate vaccines. Microbiology (Reading) 2008; 154:1170–1177 [View Article]
    [Google Scholar]
  10. Gray SJ, Trotter CL, Ramsay ME, Guiver M, Fox AJ et al. Epidemiology of meningococcal disease in England and Wales 1993/94 to 2003/04: Contribution and experiences of the meningococcal reference unit. J Med Microbiol 2006; 55:887–896 [View Article]
    [Google Scholar]
  11. Balmer P, Borrow R, Miller E. Impact of meningococcal C conjugate vaccine in the UK. J Med Microbiol 2002; 51:717–722 [View Article]
    [Google Scholar]
  12. Maiden MCJ, Ibarz-Pavón AB, Urwin R, Gray SJ, Andrews NJ et al. Impact of meningococcal serogroup c conjugate vaccines on carriage and herd immunity. J Infect Dis 2008; 197:737–743 [View Article]
    [Google Scholar]
  13. Gilmore A, Jones G, Barker M, Soltanpoor N, Stuart JM. Meningococcal disease at the University of Southampton: outbreak investigation. Epidemiol Infect 1999; 123:185–192 [View Article]
    [Google Scholar]
  14. Feavers IM, Gray SJ, Urwin R, Russell JE, Bygraves JA et al. Multilocus sequence typing and antigen gene sequencing in the investigation of a meningococcal disease outbreak. J Clin Microbiol 1999; 37:3883–3887 [View Article] [PubMed]
    [Google Scholar]
  15. Jolley KA, Hill DM, Bratcher HB, Harrison OB, Feavers IM et al. n.d Resolution of a meningococcal disease outbreak from whole-genome sequence data with rapid Web-based analysis methods. J Clin Microbiol 50:3046–3053 [View Article]
    [Google Scholar]
  16. Liu Y, Zhang D, Engström Å, Merényi G, Hagner M et al. Dynamic niche-specific adaptations in neisseria Meningitidis during infection. Microbes Infect 2016; 18:109–117 [View Article]
    [Google Scholar]
  17. Beyene GT, Kalayou S, Riaz T, Tonjum T. Comparative proteomic analysis of Neisseria meningitidis wildtype and dprA null mutant strains links DNA processing to pilus biogenesis. BMC Microbiol 2017; 17:96 [View Article]
    [Google Scholar]
  18. van Ulsen P, Kuhn K, Prinz T, Legner H, Schmid P et al. Identification of proteins of Neisseria meningitidis induced under iron-limiting conditions using the isobaric tandem mass tag (TMT) labeling approach. Proteomics 2009; 9:1771–1781 [View Article]
    [Google Scholar]
  19. Jolley KA, Maiden MCJ. BIGSdb: Scalable analysis of bacterial genome variation at the population level. BMC Bioinformatics 2010; 11:595 [View Article]
    [Google Scholar]
  20. van de Rijn I, Kessler RE. Growth characteristics of group a streptococci in a new chemically defined medium. Infect Immun 1980; 27:444–448 [View Article] [PubMed]
    [Google Scholar]
  21. Ramsey ME, Hackett KT, Kotha C, Dillard JP. New complementation constructs for inducible and constitutive gene expression in neisseria gonorrhoeae and Neisseria meningitidis. Appl Environ Microbiol 2012; 78:3068–3078 [View Article]
    [Google Scholar]
  22. Mehr IJ, Seifert HS. Differential roles of homologous recombination pathways in Neisseria gonorrhoeae pilin antigenic variation, DNA transformation and dna repair. Mol Microbiol 1998; 30:697–710 [View Article]
    [Google Scholar]
  23. Jongerius I, Lavender H, Tan L, Ruivo N, Exley RM et al. Distinct binding and immunogenic properties of the gonococcal homologue of meningococcal factor H binding protein. PLoS Pathog 2013; 9:e1003528 [View Article]
    [Google Scholar]
  24. Lavender H, Poncin K, Tang CM. Neisseria cinerea expresses a functional factor H binding protein which is recognised by immune responses elicited by meningococcal vaccines. Infect Immun 2017; 85: [View Article]
    [Google Scholar]
  25. Martin NG, Snape MD. A multicomponent serogroup B meningococcal vaccine is licensed for use in Europe: What do we know, and what are we yet to learn?. Expert Rev Vaccines 2013; 12:837–858 [View Article]
    [Google Scholar]
  26. Maslanka SE, Gheesling LL, Libutti DE, Donaldson KB, Harakeh HS et al. Standardization and a multilaboratory comparison of Neisseria meningitidis serogroup A and C serum bactericidal assays. The multilaboratory study group. Clin Diagn Lab Immunol 1997; 4:156–167 [View Article] [PubMed]
    [Google Scholar]
  27. Lucidarme J, Tan L, Exley RM, Findlow J, Borrow R et al. Characterization of Neisseria Meningitidis isolates that do not express the virulence factor and vaccine antigen factor h binding protein. Clin Vaccine Immunol 2011; 18:1002–1014 [View Article]
    [Google Scholar]
  28. Beernink PT, LoPasso C, Angiolillo A, Felici F, Granoff D. A region of the n-terminal domain of meningococcal factor h-binding protein that elicits bactericidal antibody across antigenic variant groups. Mol Immunol 2009; 46:1647–1653 [View Article]
    [Google Scholar]
  29. Seib KL, Scarselli M, Comanducci M, Toneatto D, Masignani V. Neisseria meningitidis factor h-binding protein FHBP: A key virulence factor and vaccine antigen. Expert Rev Vaccines 2015; 14:841–859 [View Article]
    [Google Scholar]
  30. Madico G, Welsch JA, Lewis LA, McNaughton A, Perlman DH et al. The meningococcal vaccine candidate gna1870 binds the complement regulatory protein factor h and enhances serum resistance. J Immunol 2006; 177:501–510 [View Article]
    [Google Scholar]
  31. Snyder LA, Cole JA, Pallen MJ. Comparative analysis of two Neisseria gonorrhoeae genome sequences reveals evidence of mobilization of Correia repeat enclosed elements and their role in regulation. BMC Genomics 2009; 10:70 [View Article]
    [Google Scholar]
  32. Tunio SA, Oldfield NJ, Berry A, Ala’Aldeen DA, Wooldridge KG et al. The moonlighting protein fructose-1, 6-bisphosphate aldolase of Neisseria meningitidis: Surface localization and role in host cell adhesion. Mol Microbiol 2010; 76:605–615 [View Article]
    [Google Scholar]
  33. Huang J, Zhu H, Wang J, Guo Y, Zhi Y et al. Fructose-1,6-bisphosphate aldolase is involved in Mycoplasma bovis colonization as a fibronectin-binding adhesin. Res Vet Sci 2019; 124:70–78 [View Article]
    [Google Scholar]
  34. Wilde S, Jiang Y, Tafoya AM, Horsman J, Yousif M et al. Salmonella-vectored vaccine delivering three Clostridium perfringens antigens protects poultry against necrotic enteritis. PLoS One 2019; 14:e0197721 [View Article]
    [Google Scholar]
  35. Ziveri J, Tros F, Guerrera IC, Chhuon C, Audry M et al. The metabolic enzyme fructose-1,6-bisphosphate aldolase acts as a transcriptional regulator in pathogenic Francisella. Nat Commun 2017; 8:853 [View Article]
    [Google Scholar]
  36. Shams F, Oldfield NJ, Lai SK, Tunio SA, Wooldridge KG et al. Fructose-1,6-bisphosphate aldolase of Neisseria meningitidis binds human plasminogen via its C-terminal lysine residue. Microbiologyopen 2016; 5:340–350 [View Article]
    [Google Scholar]
  37. Morand PC, Drab M, Rajalingam K, Nassif X, Meyer TF. Neisseria meningitidis differentially controls host cell motility through PilC1 and PilC2 components of type IV Pili. PLoS One 2009; 4:e6834 [View Article]
    [Google Scholar]
  38. Rytkönen A, Albiger B, Hansson-Palo P, Källström H, Olcén P et al. Neisseria meningitidis undergoes PilC phase variation and PilE sequence variation during invasive disease. J Infect Dis 2004; 189:402–409 [View Article]
    [Google Scholar]
  39. Coureuil M, Join-Lambert O, Lécuyer H, Bourdoulous S, Marullo S et al. Mechanism of meningeal invasion by Neisseria meningitidis. Virulence 2012; 3:164–172 [View Article]
    [Google Scholar]
  40. Jonsson AB, Nyberg G, Normark S. Phase variation of gonococcal pili by frameshift mutation in pilC, a novel gene for pilus assembly. EMBO J 1991; 10:477–488 [View Article] [PubMed]
    [Google Scholar]
  41. Rahman M, Källström H, Normark S, Jonsson AB. PilC of pathogenic Neisseria is associated with the bacterial cell surface. Mol Microbiol 1997; 25:11–25 [View Article]
    [Google Scholar]
  42. dos Santos Souza I, Maïssa N, Ziveri J, Morand PC, Coureuil M et al. Meningococcal disease: A paradigm of type‐IV pilus dependent pathogenesis. Cellular Microbiology 2020; 22:e13185 [View Article]
    [Google Scholar]
  43. Giuntini S, Vu DM, Granoff DM. fH-dependent complement evasion by disease-causing meningococcal strains with absent fHbp genes or frameshift mutations. Vaccine 2013; 31:4192–4199 [View Article]
    [Google Scholar]
  44. Lewis LA, Ngampasutadol J, Wallace R, Reid JE, Vogel U et al. The meningococcal vaccine candidate neisserial surface protein a (NspA) binds to factor H and enhances meningococcal resistance to complement. PLOS Pathog 2010 [View Article]
    [Google Scholar]
  45. Lewis LA, Vu DM, Vasudhev S, Shaughnessy J, Granoff DM et al. Factor H-dependent alternative pathway inhibition mediated by porin B contributes to virulence of Neisseria meningitidis. mBio 2013; 4:00313–e00339 [View Article]
    [Google Scholar]
  46. Loh E, Kugelberg E, Tracy A, Zhang Q, Gollan B et al. Temperature triggers immune evasion by Neisseria meningitidis. Nature 2013; 502:237–240 [View Article]
    [Google Scholar]
  47. Schneider MC, Exley RM, Ram S, Sim RB, Tang CM. Interactions between Neisseria meningitidis and the complement system. Trends Microbiol 2007; 15:233–240 [View Article]
    [Google Scholar]
  48. Schneider MC, Exley RM, Chan H, Feavers I, Kang YH et al. Functional significance of factor H binding to Neisseria meningitidis. J Immunol 2006; 176:7566–7575 [View Article]
    [Google Scholar]
  49. Granoff DM, Welsch JA, Ram S. Binding of complement factor H (fH) to Neisseria meningitidis is specific for human fH and inhibits complement activation by rat and rabbit sera. Infect Immun 2009; 77:764–769 [View Article]
    [Google Scholar]
  50. McNeil LK, Zagursky RJ, Lin SL, Murphy E, Zlotnick GW et al. Role of factor H binding protein in Neisseria meningitidis virulence and its potential as a vaccine candidate to broadly protect against meningococcal disease. Microbiol Mol Biol Rev 2013; 77:234–252 [View Article]
    [Google Scholar]
  51. Cayrou C, Akinduko AA, Mirkes EM, Lucidarme J, Clark SA et al. Clustered intergenic region sequences as predictors of factor H Binding Protein expression patterns and for assessing Neisseria meningitidis strain coverage by meningococcal vaccines. PLoS One 2018; 13:e0197186 [View Article]
    [Google Scholar]
  52. Gandhi A, Balmer P, York LJ. Characteristics of a new meningococcal serogroup B vaccine, bivalent rLP2086 (MenB-FHbp; Trumenba(R. Postgrad Med 2016; 128:548–556 [View Article]
    [Google Scholar]
  53. Siddique A, Buisine N, Chalmers R. The transposon-like correia elements encode numerous strong promoters and provide a potential new mechanism for phase variation in the meningococcus. PLoS Genet 2011; 7:e1001277 [View Article]
    [Google Scholar]
  54. Bentley SD, Vernikos GS, Snyder LA, Churcher C, Arrowsmith C et al. Meningococcal genetic variation mechanisms viewed through comparative analysis of serogroup C strain FAM18. PLoS Genet 2007; 3:e23 [View Article]
    [Google Scholar]
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