1887

Abstract

Meningococcal disease caused by serogroup B remains an important health problem in many parts of the world, and there are currently no comprehensive vaccines. Poor immunogenicity, combined with immunological identity to human sialic acids, have hindered the development of a serogroup B conjugate vaccine, resulting in the development of alternative vaccine candidates, including many outer-membrane protein (OMP)-based formulations. However, the design of protein-based meningococcal vaccines is complicated by the high level of genetic and antigenic diversity of the meningococcus. Knowledge of the extent and structuring of this diversity can have implications for the use of particular proteins as potential vaccine candidates. With this in mind, the diversity of the meningococcal OMP HmbR was investigated among isolates representative of major hyper-invasive lineages. In common with other meningococcal antigens, the genetic diversity of resulted from a combination of intraspecies horizontal genetic exchange and mutation. Furthermore, genealogical analysis showed an association of genes with clonal complexes and the occurrence of two families, A and B. Three variable regions (VR1–VR3), located in loops 2, 3 and 4, were observed with clonal complex structuring of VR types. A minority of codons (3.9 %), located within putative surface-exposed loop regions of a 2D model, were under diversifying selection, indicating regions of the protein likely to be subject to immune attack.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.036475-0
2010-05-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/micro/156/5/1384.html?itemId=/content/journal/micro/10.1099/mic.0.036475-0&mimeType=html&fmt=ahah

References

  1. Bash M. C., Lesiak K. B., Banks S. D., Frasch C. E. 1995; Analysis of Neisseria meningitidis class 3 outer membrane protein gene variable regions and type identification using genetic techniques. Infect Immun 63:1484–1490
    [Google Scholar]
  2. Bjune G., Høiby E. A., Gronnesby J. K., Arnesen O., Fredriksen J. H., Halstensen A., Holten E., Lindbak A. K., Nøkleby H. other authors 1991; Effect of outer membrane vesicle vaccine against group B meningococcal disease in Norway. Lancet 338:1093–1096
    [Google Scholar]
  3. Black J. R., Dyer D. W., Thompson M. K., Sparling P. F. 1986; Human immune response to iron-repressible outer membrane proteins of Neisseria meningitidis. Infect Immun 54:710–713
    [Google Scholar]
  4. Bracken C. S., Baer M. T., Abdur-Rashid A., Helms W., Stojiljkovic I. 1999; Use of heme–protein complexes by the Yersinia enterocolitica HemR receptor: histidine residues are essential for receptor function. J Bacteriol 181:6063–6072
    [Google Scholar]
  5. Buchanan S. K., Smith B. S., Venkatramani L., Xia D., Esser L., Palnitkar M., Chakraborty R., van der Helm D., Deisenhofer J. 1999; Crystal structure of the outer membrane active transporter FepA from Escherichia coli. Nat Struct Biol 6:56–63
    [Google Scholar]
  6. Callaghan M. J., Jolley K. A., Maiden M. C. 2006; Opacity-associated adhesin repertoire in hyperinvasive Neisseria meningitidis. Infect Immun 74:5085–5094
    [Google Scholar]
  7. Chimento D. P., Mohanty A. K., Kadner R. J., Wiener M. C. 2003; Substrate-induced transmembrane signaling in the cobalamin transporter BtuB. Nat Struct Biol 10:394–401
    [Google Scholar]
  8. Chimento D. P., Kadner R. J., Wiener M. C. 2005; Comparative structural analysis of TonB-dependent outer membrane transporters: implications for the transport cycle. Proteins 59:240–251
    [Google Scholar]
  9. Derrick J. P., Urwin R., Suker J., Feavers I. M., Maiden M. C. 1999; Structural and evolutionary inference from molecular variation in Neisseria porins. Infect Immun 67:2406–2413
    [Google Scholar]
  10. Didelot X., Falush D. 2007; Inference of bacterial microevolution using multilocus sequence data. Genetics 175:1251–1266
    [Google Scholar]
  11. Embley T. M. 1991; The linear PCR reaction: a simple and robust method for sequencing amplified rRNA genes. Lett Appl Microbiol 13:171–174
    [Google Scholar]
  12. Feavers I. M., Suker J., McKenna A. J., Heath A. B., Maiden M. C. 1992; Molecular analysis of the serotyping antigens of Neisseria meningitidis. Infect Immun 60:3620–3629
    [Google Scholar]
  13. Ferguson A. D., Hofmann E., Coulton J. W., Diederichs K., Welte W. 1998; Siderophore-mediated iron transport: crystal structure of FhuA with bound lipopolysaccharide. Science 282:2215–2220
    [Google Scholar]
  14. Ferguson A. D., Chakraborty R., Smith B. S., Esser L., van der Helm D., Deisenhofer J. 2002; Structural basis of gating by the outer membrane transporter FecA. Science 295:1715–1719
    [Google Scholar]
  15. Finne J., Leinonen M., Makela P. H. 1983; Antigenic similarities between brain components and bacteria causing meningitis. Implications for vaccine development and pathogenesis. Lancet 2:355–357
    [Google Scholar]
  16. Frasch C. E., Tsai C. M., Mocca L. F. 1986; Outer membrane proteins of Neisseria meningitidis: structure and importance in meningococcal disease. Clin Invest Med 9:101–107
    [Google Scholar]
  17. Gupta S., Maiden M. C. 2001; Exploring the evolution of diversity in pathogen populations. Trends Microbiol 9:181–185
    [Google Scholar]
  18. Gupta S., Maiden M. C., Feavers I. M., Nee S., May R. M., Anderson R. M. 1996; The maintenance of strain structure in populations of recombining infectious agents. Nat Med 2:437–442
    [Google Scholar]
  19. Harrison O. B., Evans N. J., Blair J. M., Grimes H. S., Tinsley C. R., Nassif X., Kriz P., Ure R., Gray S. J. other authors 2009; Epidemiological evidence for the role of the hemoglobin receptor, HmbR, in Meningococcal virulence. J Infect Dis 200:94–98
    [Google Scholar]
  20. Hasegawa M., Kishino H., Yano T. 1985; Dating of the human–ape splitting by a molecular clock of mitochondrial DNA. J Mol Evol 22:160–174
    [Google Scholar]
  21. Izadi-Pruneyre N., Huche F., Lukat-Rodgers G. S., Lecroisey A., Gilli R., Rodgers K. R., Wandersman C., Delepelaire P. 2006; The heme transfer from the soluble HasA hemophore to its membrane-bound receptor HasR is driven by protein–protein interaction from a high to a lower affinity binding site. J Biol Chem 281:25541–25550
    [Google Scholar]
  22. Jacobsson S., Molling P., Olcen P. 2009; Seroprevalence of antibodies against fHbp and NadA, two potential vaccine antigens for Neisseria meningitidis. Vaccine 27:5755–5759
    [Google Scholar]
  23. Jodar L., Feavers I. M., Salisbury D., Granoff D. M. 2002; Development of vaccines against meningococcal disease. Lancet 359:1499–1508
    [Google Scholar]
  24. Jolley K. A., Feil E. J., Chan M. S., Maiden M. C. 2001; Sequence type analysis and recombinational tests (START. Bioinformatics 17:1230–1231
    [Google Scholar]
  25. Krieg S., Huche F., Diederichs K., Izadi-Pruneyre N., Lecroisey A., Wandersman C., Delepelaire P., Welte W. 2009; Heme uptake across the outer membrane as revealed by crystal structures of the receptor–hemophore complex. Proc Natl Acad Sci U S A 106:1045–1050
    [Google Scholar]
  26. Legrain M., Mazarin V., Irwin S. W., Bouchon B., Quentin-Millet M. J., Jacobs E., Schryvers A. B. 1993; Cloning and characterization of Neisseria meningitidis genes encoding the transferrin-binding proteins Tbp1 and Tbp2. Gene 130:73–80
    [Google Scholar]
  27. Lewis L. A., Gray E., Wang Y. P., Roe B. A., Dyer D. W. 1997; Molecular characterization of hpuAB, the haemoglobin–haptoglobin-utilization operon of Neisseria meningitidis. Mol Microbiol 23:737–749
    [Google Scholar]
  28. Lewis L. A., Gipson M., Hartman K., Ownbey T., Vaughn J., Dyer D. W. 1999; Phase variation of HpuAB and HmbR, two distinct haemoglobin receptors of Neisseria meningitidis DNM2. Mol Microbiol 32:977–989
    [Google Scholar]
  29. Locher K. P., Rees B., Koebnik R., Mitschler A., Moulinier L., Rosenbusch J. P., Moras D. 1998; Transmembrane signaling across the ligand-gated FhuA receptor: crystal structures of free and ferrichrome-bound states reveal allosteric changes. Cell 95:771–778
    [Google Scholar]
  30. Madico G., Welsch J. A., Lewis L. A., McNaughton A., Perlman D. H., Costello C. E., Ngampasutadol J., Vogel U., Granoff D. M., Ram S. 2006; The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance. J Immunol 177:501–510
    [Google Scholar]
  31. Maiden M. C., Bygraves J. A., Feil E., Morelli G., Russell J. E., Urwin R., Zhang Q., Zhou J., Zurth K. other authors 1998; Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms. Proc Natl Acad Sci U S A 95:3140–3145
    [Google Scholar]
  32. Martelli P. L., Fariselli P., Krogh A., Casadio R. 2002; A sequence-profile-based HMM for predicting and discriminating β barrel membrane proteins. Bioinformatics 18 (Suppl. 1):S46–S53
    [Google Scholar]
  33. McGuinness B. T., Lambden P. R., Heckels J. E. 1993; Class 1 outer membrane protein of Neisseria meningitidis: epitope analysis of the antigenic diversity between strains, implications for subtype definition and molecular epidemiology. Mol Microbiol 7:505–514
    [Google Scholar]
  34. Mitka M. 2005; New vaccine should ease meningitis fears. JAMA 293:1433–1434
    [Google Scholar]
  35. Nielsen R., Yang Z. 1998; Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. Genetics 148:929–936
    [Google Scholar]
  36. Perkins-Balding D., Baer M. T., Stojiljkovic I. 2003; Identification of functionally important regions of a haemoglobin receptor from Neisseria meningitidis. Microbiology 149:3423–3435
    [Google Scholar]
  37. Pettersson A., Kortekaas J., Weynants V. E., Voet P., Poolman J. T., Bos M. P., Tommassen J. 2006; Vaccine potential of the Neisseria meningitidis lactoferrin-binding proteins LbpA and LbpB. Vaccine 24:3545–3557
    [Google Scholar]
  38. Prinz T., Meyer M., Pettersson A., Tommassen J. 1999; Structural characterization of the lactoferrin receptor from Neisseria meningitidis. J Bacteriol 181:4417–4419
    [Google Scholar]
  39. Rokbi B., Mignon M., Maitre-Wilmotte G., Lissolo L., Danve B., Caugant D. A., Quentin-Millet M. J. 1997; Evaluation of recombinant transferrin-binding protein B variants from Neisseria meningitidis for their ability to induce cross-reactive and bactericidal antibodies against a genetically diverse collection of serogroup B strains. Infect Immun 65:55–63
    [Google Scholar]
  40. Sacchi C. T., Lemos A. P., Whitney A. M., Solari C. A., Brandt M. E., Melles C. E., Frasch C. E., Mayer L. W. 1998; Correlation between serological and sequencing analyses of the PorB outer membrane protein in the Neisseria meningitidis serotyping system. Clin Diagn Lab Immunol 5:348–354
    [Google Scholar]
  41. Schmidt H. A., Strimmer K., Vingron M., von Haeseler A. 2002; tree-puzzle: maximum likelihood phylogenetic analysis using quartets and parallel computing. Bioinformatics 18:502–504
    [Google Scholar]
  42. Sierra G. V., Campa H. C., Varcacel N. M., Garcia I. L., Izquierdo P. L., Sotolongo P. F., Casanueva G. V., Rico C. O., Rodriguez C. R., Terry M. H. 1991; Vaccine against group B Neisseria meningitidis: protection trial and mass vaccination results in Cuba. NIPH Ann 14:195–207 discussion 208–110
    [Google Scholar]
  43. Staden R. 1996; The Staden sequence analysis package. Mol Biotechnol 5:233–241
    [Google Scholar]
  44. Stojiljkovic I., Hwa V., de Saint Martin L., O'Gaora P., Nassif X., Heffron F., So M. 1995; The Neisseria meningitidis haemoglobin receptor: its role in iron utilization and virulence. Mol Microbiol 15:531–541
    [Google Scholar]
  45. Stojiljkovic I., Larson J., Hwa V., Anic S., So M. 1996; HmbR outer membrane receptors of pathogenic Neisseria spp.: iron-regulated, hemoglobin-binding proteins with a high level of primary structure conservation. J Bacteriol 178:4670–4678
    [Google Scholar]
  46. Suker J., Feavers I. M., Achtman M., Morelli G., Wang J. F., Maiden M. C. 1994; The porA gene in serogroup A meningococci: evolutionary stability and mechanism of genetic variation. Mol Microbiol 12:253–265
    [Google Scholar]
  47. Suzuki Y., Nei M. 2004; False-positive selection identified by ML-based methods: examples from the Sig1 gene of the diatom Thalassiosira weissflogii and the tax gene of a human T-cell lymphotropic virus. Mol Biol Evol 21:914–921
    [Google Scholar]
  48. Tamura K., Dudley J., Nei M., Kumar S. 2007; mega4: Molecular Evolutionary Genetics Analysis (mega) software version 4.0. Mol Biol Evol 24:1596–1599
    [Google Scholar]
  49. Tappero J. W., Lagos R., Ballesteros A. M., Plikaytis B., Williams D., Dykes J., Gheesling L. L., Carlone G. M., Høiby E. A. other authors 1999; Immunogenicity of 2 serogroup B outer-membrane protein meningococcal vaccines: a randomized controlled trial in Chile. JAMA 281:1520–1527
    [Google Scholar]
  50. Thompson J. D., Higgins D. G., Gibson T. J. 1994; clustal w: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680
    [Google Scholar]
  51. Thornton V., Lennon D., Rasanathan K., O'Hallahan J., Oster P., Stewart J., Tilman S., Aaberge I., Feiring B. other authors 2006; Safety and immunogenicity of New Zealand strain meningococcal serogroup B OMV vaccine in healthy adults: beginning of epidemic control. Vaccine 24:1395–1400
    [Google Scholar]
  52. Tzeng Y. L., Stephens D. S. 2000; Epidemiology and pathogenesis of Neisseria meningitidis. Microbes Infect 2:687–700
    [Google Scholar]
  53. Urwin R., Russell J. E., Thompson E. A., Holmes E. C., Feavers I. M., Maiden M. C. 2004; Distribution of surface protein variants among hyperinvasive meningococci: implications for vaccine design. Infect Immun 72:5955–5962
    [Google Scholar]
  54. Wedege E., Høiby E. A., Rosenqvist E., Bjune G. 1998; Immune responses against major outer membrane antigens of Neisseria meningitidis in vaccinees and controls who contracted meningococcal disease during the Norwegian serogroup B protection trial. Infect Immun 66:3223–3231
    [Google Scholar]
  55. Wilson D. J., McVean G. 2006; Estimating diversifying selection and functional constraint in the presence of recombination. Genetics 172:1411–1425
    [Google Scholar]
  56. Womble D. D. 2000; GCG: The Wisconsin Package of sequence analysis programs. Methods Mol Biol 132:3–22
    [Google Scholar]
  57. Wong W. S., Yang Z., Goldman N., Nielsen R. 2004; Accuracy and power of statistical methods for detecting adaptive evolution in protein coding sequences and for identifying positively selected sites. Genetics 168:1041–1051
    [Google Scholar]
  58. Yang Z. 1997; PAML: a program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 13:555–556
    [Google Scholar]
  59. Yang Z., Nielsen R., Goldman N., Pedersen A. M. 2000; Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics 155:431–449
    [Google Scholar]
  60. Yang Z., Wong W. S., Nielsen R. 2005; Bayes empirical Bayes inference of amino acid sites under positive selection. Mol Biol Evol 22:1107–1118
    [Google Scholar]
  61. Zapata G. A., Vann W. F., Rubinstein Y., Frasch C. E. 1992; Identification of variable region differences in Neisseria meningitidis class 3 protein sequences among five group B serotypes. Mol Microbiol 6:3493–3499
    [Google Scholar]
  62. Zhang J. 2004; Frequent false detection of positive selection by the likelihood method with branch-site models. Mol Biol Evol 21:1332–1339
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.036475-0
Loading
/content/journal/micro/10.1099/mic.0.036475-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Supplementary material 2

PDF

Supplementary material 3

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error