1887

Abstract

A new generation of vaccines containing multiple protein components that aim to provide broad protection against serogroup B meningococci has been developed. One candidate, 4CMenB (4 Component MenB), has been approved by the European Medicines Agency, but is predicted to provide at most 70–80 % strain coverage; hence there is a need for second-generation vaccines that achieve higher levels of coverage. Prior knowledge of the diversity of potential protein vaccine components is a key step in vaccine design. A number of iron import systems have been targeted in meningococcal vaccine development, including the HmbR and HpuAB outer-membrane proteins, which mediate the utilization of haemoglobin or haemoglobin–haptoglobin complexes as iron sources. While the genetic diversity of HmbR has been described, little is known of the diversity of HpuAB. Using whole genome sequences deposited in a Bacterial Isolate Genome Sequence Database (BIGSDB), the prevalence and diversity of HpuAB among were investigated. HpuAB was widely present in a range of species whereas HmbR was mainly limited to the pathogenic species and . Patterns of sequence variation in sequences from HpuAB proteins were suggestive of recombination and diversifying selection consistent with strong immune selection. HpuAB was subject to repeat-mediated phase variation in pathogenic and the closely related non-pathogenic species and but not in the majority of other commensal species. These findings are consistent with HpuAB being subject to frequent genetic transfer potentially limiting the efficacy of this receptor as a vaccine candidate.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.068874-0
2013-09-01
2024-04-26
Loading full text...

Full text loading...

/deliver/fulltext/micro/159/9/1920.html?itemId=/content/journal/micro/10.1099/mic.0.068874-0&mimeType=html&fmt=ahah

References

  1. Altschul S. F., Madden T. L., Schäffer A. A., Zhang J., Zhang Z., Miller W., Lipman D. J.( 1997). Gapped blastand psi-blast: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402 [View Article][PubMed]
    [Google Scholar]
  2. Anderson J. E., Sparling P. F., Cornelissen C. N.( 1994). Gonococcal transferrin-binding protein 2 facilitates but is not essential for transferrin utilization. J Bacteriol 176:3162–3170[PubMed]
    [Google Scholar]
  3. Arnold K., Bordoli L., Kopp J., Schwede T.( 2006). The swiss-model workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22:195–201 [View Article][PubMed]
    [Google Scholar]
  4. Bennett J. S., Griffiths D. T., McCarthy N. D., Sleeman K. L., Jolley K. A., Crook D. W., Maiden M. C.( 2005). Genetic diversity and carriage dynamics of Neisseria lactamica in infants. Infect Immun 73:2424–2432 [View Article][PubMed]
    [Google Scholar]
  5. Bennett J. S., Thompson E. A., Kriz P., Jolley K. A., Maiden M. C.( 2009). A common gene pool for the Neisseria FetA antigen. Int J Med Microbiol 299:133–139 [View Article][PubMed]
    [Google Scholar]
  6. Bennett J. S., Jolley K. A., Earle S. G., Corton C., Bentley S. D., Parkhill J., Maiden M. C.( 2012). A genomic approach to bacterial taxonomy: an examination and proposed reclassification of species within the genus Neisseria.. Microbiology 158:1570–1580 [View Article][PubMed]
    [Google Scholar]
  7. Berger U.( 1971). [Neisseria mucosa var. heidelbergensis]. Z Med Mikrobiol Immunol 156:154–158 [View Article][PubMed]
    [Google Scholar]
  8. Biswas G. D., Anderson J. E., Chen C. J., Cornelissen C. N., Sparling P. F.( 1999). Identification and functional characterization of the Neisseria gonorrhoeae lbpB gene product. Infect Immun 67:455–459[PubMed]
    [Google Scholar]
  9. 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[PubMed]
    [Google Scholar]
  10. Budroni S., Siena E., Dunning Hotopp J. C., Seib K. L., Serruto D., Nofroni C., Comanducci M., Riley D. R., Daugherty S. C.& other authors ( 2011). Neisseria meningitidis is structured in clades associated with restriction modification systems that modulate homologous recombination. Proc Natl Acad Sci U S A 108:4494–4499 [View Article][PubMed]
    [Google Scholar]
  11. Calmettes C., Alcantara J., Yu R. H., Schryvers A. B., Moraes T. F.( 2012). The structural basis of transferrin sequestration by transferrin-binding protein B. Nat Struct Mol Biol 19:358–360 [View Article][PubMed]
    [Google Scholar]
  12. Caugant D. A., Maiden M. C.( 2009). Meningococcal carriage and disease – population biology and evolution. Vaccine 27:Suppl 2B64–B70 [View Article][PubMed]
    [Google Scholar]
  13. Chen C. J., Elkins C., Sparling P. F.( 1998). Phase variation of hemoglobin utilization in Neisseria gonorrhoeae.. Infect Immun 66:987–993[PubMed]
    [Google Scholar]
  14. Chen C. J., Mclean D., Thomas C. E., Anderson J. E., Sparling P. F.( 2002). Point mutations in HpuB enable gonococcal HpuA deletion mutants to grow on hemoglobin. J Bacteriol 184:420–426 [View Article][PubMed]
    [Google Scholar]
  15. Chisholm S. A., Unemo M., Quaye N., Johansson E., Cole M. J., Ison C. A., Van de Laar M. J.( 2013). Molecular epidemiological typing within the European Gonococcal Antimicrobial Resistance Surveillance Programme reveals predominance of a multidrug-resistant clone. Euro surveillance: bulletin europeen sur les maladies transmissibles  =  European communicable disease bulletin
    [Google Scholar]
  16. Cobessi D., Meksem A., Brillet K.( 2010). Structure of the heme/hemoglobin outer membrane receptor ShuA from Shigella dysenteriae: heme binding by an induced fit mechanism. Proteins 78:286–294 [View Article][PubMed]
    [Google Scholar]
  17. Cornelissen C. N., Kelley M., Hobbs M. M., Anderson J. E., Cannon J. G., Cohen M. S., Sparling P. F.( 1998). The transferrin receptor expressed by gonococcal strain FA1090 is required for the experimental infection of human male volunteers. Mol Microbiol 27:611–616 [View Article][PubMed]
    [Google Scholar]
  18. Cornelissen C. N., Hollander A.( 2011). TonB-dependent transporters expressed by Neisseria gonorrhoeae. Front Microbiol 2:1–13 [View Article][PubMed]
    [Google Scholar]
  19. Criss A. K., Seifert H. S.( 2012). A bacterial siren song: intimate interactions between Neisseria and neutrophils. Nat Rev Microbiol 10:178–190 [View Article][PubMed]
    [Google Scholar]
  20. Evans N. J., Harrison O. B., Clow K., Derrick J. P., Feavers I. M., Maiden M. C. J.( 2010). Variation and molecular evolution of HmbR, the Neisseria meningitidis haemoglobin receptor. Microbiology 156:1384–1393 [View Article][PubMed]
    [Google Scholar]
  21. 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 [View Article][PubMed]
    [Google Scholar]
  22. Harrison O. B., Claus H., Jiang Y., Bennett J. S., Bratcher H. B., Jolley K. A., Corton C., Care R., Poolman J. T.& other authors ( 2013). Description and nomenclature of Neisseria meningitidis capsule locus. Emerg Infect Dis 19:566–573 [View Article][PubMed]
    [Google Scholar]
  23. Huson D. H., Bryant D.( 2006). Application of phylogenetic networks in evolutionary studies. Mol Biol Evol 23:254–267 [View Article][PubMed]
    [Google Scholar]
  24. Jolley K. A., Hill D. M., Bratcher H. B., Harrison O. B., Feavers I. M., Parkhill J., Maiden M. C.( 2012). 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][PubMed]
    [Google Scholar]
  25. Lewis D. A.( 2010). The Gonococcus fights back: is this time a knock out?. Sex Transm Infect 86:415–421 [View Article][PubMed]
    [Google Scholar]
  26. 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 [View Article][PubMed]
    [Google Scholar]
  27. 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 [View Article][PubMed]
    [Google Scholar]
  28. Linz B., Schenker M., Zhu P., Achtman M.( 2000). Frequent interspecific genetic exchange between commensal Neisseriae and Neisseria meningitidis.. Mol Microbiol 36:1049–1058 [View Article][PubMed]
    [Google Scholar]
  29. Lucidarme J., Comanducci M., Findlow J., Gray S. J., Kaczmarski E. B., Guiver M., Vallely P. J., Oster P., Pizza M.& other authors ( 2010). Characterization of fHbp, nhba (gna2132), nadA, porA, and sequence type in group B meningococcal case isolates collected in England and Wales during January 2008 and potential coverage of an investigational group B meningococcal vaccine. Clin Vaccine Immunol 17:919–929 [View Article][PubMed]
    [Google Scholar]
  30. Maiden M. C. J., Malorny B., Achtman M.( 1996). A global gene pool in the Neisseriae.. Mol Microbiol 21:1297–1298 [View Article][PubMed]
    [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 [View Article][PubMed]
    [Google Scholar]
  32. Noinaj N., Guillier M., Barnard T. J., Buchanan S. K.( 2010). TonB-dependent transporters: regulation, structure, and function. Annu Rev Microbiol 64:43–60 [View Article][PubMed]
    [Google Scholar]
  33. Noinaj N., Buchanan S. K., Cornelissen C. N.( 2012a). The transferrin–iron import system from pathogenic Neisseria species. Mol Microbiol 86:246–257 [View Article][PubMed]
    [Google Scholar]
  34. Noinaj N., Easley N. C., Oke M., Mizuno N., Gumbart J., Boura E., Steere A. N., Zak O., Aisen P.& other authors ( 2012b). Structural basis for iron piracy by pathogenic Neisseria.. Nature 483:53–58 [View Article][PubMed]
    [Google Scholar]
  35. 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 [View Article][PubMed]
    [Google Scholar]
  36. Perkins-Balding D., Ratliff-Griffin M., Stojiljkovic I.( 2004). Iron transport systems in Neisseria meningitidis.. Microbiol Mol Biol Rev 68:154–171 [View Article][PubMed]
    [Google Scholar]
  37. Pollard A. J.( 2004). Global epidemiology of meningococcal disease and vaccine efficacy. Pediatr Infect Dis J 23:SupplS274–S279[PubMed]
    [Google Scholar]
  38. Richmond P. C., Marshall H. S., Nissen M. D., Jiang Q., Jansen K. U., Garcés-Sánchez M., Martinón-Torres F., Beeslaar J., Szenborn L.& other authors ( 2012). Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis 12:597–607 [View Article][PubMed]
    [Google Scholar]
  39. Rokbi B., Mignon M., Caugant D. A., Quentin-Millet M. J.( 1997). Heterogeneity of tbpB, the transferrin-binding protein B gene, among serogroup B Neisseria meningitidis strains of the ET-5 complex. Clin Diagn Lab Immunol 4:522–529[PubMed]
    [Google Scholar]
  40. Saleem M., Prince S. M., Rigby S. E., Imran M., Patel H., Chan H., Sanders H., Maiden M. C., Feavers I. M., Derrick J. P.( 2013). Use of a molecular decoy to segregate transport from antigenicity in the FrpB iron transporter from Neisseria meningitidis.. PLoS ONE 8:e56746 [View Article][PubMed]
    [Google Scholar]
  41. Serruto D., Bottomley M. J., Ram S., Giuliani M. M., Rappuoli R.( 2012). The new multicomponent vaccine against meningococcal serogroup B, 4CMenB: immunological, functional and structural characterization of the antigens. Vaccine 30:Suppl 2B87–B97 [View Article][PubMed]
    [Google Scholar]
  42. 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 [View Article][PubMed]
    [Google Scholar]
  43. Tamura K., Peterson D., Peterson N., Stecher G., Nei M., Kumar S.( 2011). mega5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739 [View Article][PubMed]
    [Google Scholar]
  44. Tauseef I., Harrison O. B., Wooldridge K. G., Feavers I. M., Neal K. R., Gray S. J., Kriz P., Turner D. P., Ala’Aldeen D. A.& other authors ( 2011). Influence of the combination and phase variation status of the haemoglobin receptors HmbR and HpuAB on meningococcal virulence. Microbiology 157:1446–1456 [View Article][PubMed]
    [Google Scholar]
  45. 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 [View Article][PubMed]
    [Google Scholar]
  46. Vogel U., Taha M. K., Vazquez J. A., Findlow J., Claus H., Stefanelli P., Caugant D. A., Kriz P., Abad R.& other authors ( 2013). Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment. Lancet Infect Dis 13:416–425 [View Article][PubMed]
    [Google Scholar]
  47. Wilson D. J., McVean G.( 2006). Estimating diversifying selection and functional constraint in the presence of recombination. Genetics 172:1411–1425 [View Article][PubMed]
    [Google Scholar]
  48. Wolfgang W. J., Passaretti T. V., Jose R., Cole J., Coorevits A., Carpenter A. N., Jose S., Van Landschoot A., Izard J.& other authors ( 2013). Neisseria oralis sp. nov., isolated from healthy gingival plaque and clinical samples. Int J Syst Evol Microbiol 63:1323–1328 [View Article][PubMed]
    [Google Scholar]
  49. Zerbino D. R.( 2010). Using the Velvet de novo assembler for short-read sequencing technologies. Curr Protoc Bioinformatics Chapter 11:5.1–5.12[PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.068874-0
Loading
/content/journal/micro/10.1099/mic.0.068874-0
Loading

Data & Media loading...

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