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. 1996 Mar;64(3):980–986. doi: 10.1128/iai.64.3.980-986.1996

Immune selection for antigenic drift of major outer membrane protein P2 of Haemophilus influenzae during persistence in subcutaneous tissue cages in rabbits.

L Vogel 1, B Duim 1, F Geluk 1, P Eijk 1, H Jansen 1, J Dankert 1, L vanAlphen 1
PMCID: PMC173866  PMID: 8641810

Abstract

During persistence of nonencapsulated Haemophilus influenzae in the respiratory tracts of patients with chronic bronchitis, the major outer membrane proteins (MOMPs) P2 and P5 show antigenic drift. The hypothesis that appearance of antigenic variants is the consequence of antibody-dependent selection was tested in a rabbit model. Persistence of H. influenzae d1 was achieved in subcutaneous tissue cages for up to 948 days. During persistence in the rabbits, similar changes in MOMP P2 of H. influenzae occurred, as observed in isolates from chronic bronchitis patients. In rabbits vaccinated with strain d3 and in nonvaccinated rabbits, antigenic drift occurred later than in rabbits vaccinated with strain d1. High titers of antibodies against H. influenzae were measured in tissue cage fluid and serum. Vaccination of the rabbits with H. influenzae d1 or d3, an antigenic variant of strain d1, resulted neither in eradication of H. influenzae d1 nor in increased antibody titers in serum and tissue cage fluid. The sera of nonvaccinated rabbits during persistence had no strain d1-specific bactericidal activity in the presence of complement. Vaccination with H. influenzae d1 induced serum bactericidal activity against strain d1 in the presence of complement. However, a variant of strain d1 appearing in the tissue cages was not killed by this serum bactericidal activity. We conclude that immunological pressure leads to the selection of MOMP variants of H. influenzae and that these variants escape the antibody-mediated strain-specific bactericidal activity against H. influenzae.

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Selected References

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  1. Brandtzaeg P. Humoral immune response patterns of human mucosae: induction and relation to bacterial respiratory tract infections. J Infect Dis. 1992 Jun;165 (Suppl 1):S167–S176. doi: 10.1093/infdis/165-supplement_1-s167. [DOI] [PubMed] [Google Scholar]
  2. Bruderer U., Cryz S. J., Jr, Schaad U. B., Deusinger M., Que J. U., Lang A. B. Affinity constants of naturally acquired and vaccine-induced anti-Pseudomonas aeruginosa antibodies in healthy adults and cystic fibrosis patients. J Infect Dis. 1992 Aug;166(2):344–349. doi: 10.1093/infdis/166.2.344. [DOI] [PubMed] [Google Scholar]
  3. Costerton J. W., Geesey G. G., Cheng K. J. How bacteria stick. Sci Am. 1978 Jan;238(1):86–95. doi: 10.1038/scientificamerican0178-86. [DOI] [PubMed] [Google Scholar]
  4. Duim B., van Alphen L., Eijk P., Jansen H. M., Dankert J. Antigenic drift of non-encapsulated Haemophilus influenzae major outer membrane protein P2 in patients with chronic bronchitis is caused by point mutations. Mol Microbiol. 1994 Mar;11(6):1181–1189. doi: 10.1111/j.1365-2958.1994.tb00394.x. [DOI] [PubMed] [Google Scholar]
  5. Gnehm H. E., Pelton S. I., Gulati S., Rice P. A. Characterization of antigens from nontypable Haemophilus influenzae recognized by human bactericidal antibodies. Role of Haemophilus outer membrane proteins. J Clin Invest. 1985 May;75(5):1645–1658. doi: 10.1172/JCI111872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Groeneveld K., Eijk P. P., van Alphen L., Jansen H. M., Zanen H. C. Haemophilus influenzae infections in patients with chronic obstructive pulmonary disease despite specific antibodies in serum and sputum. Am Rev Respir Dis. 1990 May;141(5 Pt 1):1316–1321. doi: 10.1164/ajrccm/141.5_Pt_1.1316. [DOI] [PubMed] [Google Scholar]
  7. Groeneveld K., van Alphen L., Eijk P. P., Jansen H. M., Zanen H. C. Changes in outer membrane proteins of nontypable Haemophilus influenzae in patients with chronic obstructive pulmonary disease. J Infect Dis. 1988 Aug;158(2):360–365. doi: 10.1093/infdis/158.2.360. [DOI] [PubMed] [Google Scholar]
  8. Groeneveld K., van Alphen L., Eijk P. P., Visschers G., Jansen H. M., Zanen H. C. Endogenous and exogenous reinfections by Haemophilus influenzae in patients with chronic obstructive pulmonary disease: the effect of antibiotic treatment on persistence. J Infect Dis. 1990 Mar;161(3):512–517. doi: 10.1093/infdis/161.3.512. [DOI] [PubMed] [Google Scholar]
  9. Groeneveld K., van Alphen L., Voorter C., Eijk P. P., Jansen H. M., Zanen H. C. Antigenic drift of Haemophilus influenzae in patients with chronic obstructive pulmonary disease. Infect Immun. 1989 Oct;57(10):3038–3044. doi: 10.1128/iai.57.10.3038-3044.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kagan E., Soskolne C. L., Zwi S., Hurwitz S., Maier G. M., Ipp T., Rabson A. R. Immunologic studies in patients with recurrent bronchopulmonary infections. Am Rev Respir Dis. 1975 Apr;111(4):441–451. doi: 10.1164/arrd.1975.111.4.441. [DOI] [PubMed] [Google Scholar]
  11. Katz S., Izhar M., Mirelman D. Bacterial adherence to surgical sutures. A possible factor in suture induced infection. Ann Surg. 1981 Jul;194(1):35–41. doi: 10.1097/00000658-198107000-00007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lugtenberg B., Meijers J., Peters R., van der Hoek P., van Alphen L. Electrophoretic resolution of the "major outer membrane protein" of Escherichia coli K12 into four bands. FEBS Lett. 1975 Oct 15;58(1):254–258. doi: 10.1016/0014-5793(75)80272-9. [DOI] [PubMed] [Google Scholar]
  13. Murphy T. F., Sethi S. Bacterial infection in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1992 Oct;146(4):1067–1083. doi: 10.1164/ajrccm/146.4.1067. [DOI] [PubMed] [Google Scholar]
  14. Musher D. M., Hague-Park M., Baughn R. E., Wallace R. J., Jr, Cowley B. Opsonizing and bactericidal effects of normal human serum on nontypable Haemophilus influenzae. Infect Immun. 1983 Jan;39(1):297–304. doi: 10.1128/iai.39.1.297-304.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Möller L. V., Regelink A. G., Grasselier H., Dankert-Roelse J. E., Dankert J., van Alphen L. Multiple Haemophilus influenzae strains and strain variants coexist in the respiratory tract of patients with cystic fibrosis. J Infect Dis. 1995 Nov;172(5):1388–1392. doi: 10.1093/infdis/172.5.1388. [DOI] [PubMed] [Google Scholar]
  16. Out T. A., Jansen H. M., van Steenwijk R. P., de Nooijer M. J., van de Graaf E. A., Zuijderhoudt F. M. ELISA of ceruloplasmin and alpha-2-macroglobulin in paired bronchoalveolar lavage fluid and serum samples. Clin Chim Acta. 1987 Jun 15;165(2-3):277–288. doi: 10.1016/0009-8981(87)90172-0. [DOI] [PubMed] [Google Scholar]
  17. Troelstra A., Vogel L., van Alphen L., Eijk P., Jansen H., Dankert J. Opsonic antibodies to outer membrane protein P2 of nonencapsulated Haemophilus influenza are strain specific. Infect Immun. 1994 Mar;62(3):779–784. doi: 10.1128/iai.62.3.779-784.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Turk D. C. The pathogenicity of Haemophilus influenzae. J Med Microbiol. 1984 Aug;18(1):1–16. doi: 10.1099/00222615-18-1-1. [DOI] [PubMed] [Google Scholar]
  19. Veale D. R., Smith H., Witt K. A., Marshall R. B. Differential ability of colonial types of Neisseria gonorrhoeae to produce infection cutaneous perforated plastic chambers in guinea-pigs and rabbits. J Med Microbiol. 1975 May;8(2):325–335. doi: 10.1099/00222615-8-2-325. [DOI] [PubMed] [Google Scholar]
  20. Vogel L., van Alphen L., Geluk F., Troelstra A., Martin E., Bredius R., Eijk P., Jansen H., Dankert J. Quantitative flow cytometric analysis of opsonophagocytosis and killing of nonencapsulated Haemophilus influenzae by human polymorphonuclear leukocytes. Clin Diagn Lab Immunol. 1994 Jul;1(4):394–400. doi: 10.1128/cdli.1.4.394-400.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Wagner M., Wagner B., Bergholm A. M., Holm S. E. Experimental infection with group B streptococci in tissue cages implanted in rabbits. Zentralbl Bakteriol Mikrobiol Hyg A. 1984 Dec;258(2-3):242–255. doi: 10.1016/s0176-6724(84)80042-5. [DOI] [PubMed] [Google Scholar]
  22. Wallace F. J., Clancy R. L., Cripps A. W. An animal model demonstration of enhanced clearance of nontypable Haemophilus influenzae from the respiratory tract after antigen stimulation of gut-associated lymphoid tissue. Am Rev Respir Dis. 1989 Aug;140(2):311–316. doi: 10.1164/ajrccm/140.2.311. [DOI] [PubMed] [Google Scholar]
  23. Zimmerli W., Lew P. D., Waldvogel F. A. Pathogenesis of foreign body infection. Evidence for a local granulocyte defect. J Clin Invest. 1984 Apr;73(4):1191–1200. doi: 10.1172/JCI111305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Zimmerli W., Waldvogel F. A., Vaudaux P., Nydegger U. E. Pathogenesis of foreign body infection: description and characteristics of an animal model. J Infect Dis. 1982 Oct;146(4):487–497. doi: 10.1093/infdis/146.4.487. [DOI] [PubMed] [Google Scholar]
  25. van Alphen L., Eijk P., Geelen-van den Broek L., Dankert J. Immunochemical characterization of variable epitopes of outer membrane protein P2 of nontypeable Haemophilus influenzae. Infect Immun. 1991 Jan;59(1):247–252. doi: 10.1128/iai.59.1.247-252.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. van Alphen L., Riemens T., Poolman J., Zanen H. C. Characteristics of major outer membrane proteins of Haemophilus influenzae. J Bacteriol. 1983 Aug;155(2):878–885. doi: 10.1128/jb.155.2.878-885.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]

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