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Variable major lipoprotein is a principal TNF-inducing factor of louse-borne relapsing fever

Abstract

Massive release of tumor necrosis factor is responsible for the potentially fatal Jarisch-Herxheimer reaction that follows antibiotic treatment of relapsing fever due to Borrelia recurrentis . We have undertaken the quantitative purification of the components of B. recurrentis that stimulate human monocytes to produce tumor necrosis factor. We show that the predominant factor inducing tumor necrosis factor is a variable lipoprotein homologous to the variable major protein of B. hermsii . We found antibodies to different forms of variable major protein in two patients with louse-borne relapsing fever. The three purified variable major proteins studied here differ in their ability to induce tumor necrosis factor production, which may partly explain the variable clinical severity of borrelial infection. These results may be of considerable relevance for the pathogenesis of Lyme disease and other forms of human borreliosis.

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Figure 1: Extraction and properties of the TNF-inducing activity.
Figure 2: Purification of the TNF-inducing factor.
Figure 3: Alignment of partial peptide sequence from B.recurrentis isolate A1 with that of vmp12 of B. hermsii.
Figure 4: Vmp is the TNF-inducing molecule.
Figure 5: Vmps are expressed in the host and elicit different TNF responses in vitro.

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References

  1. Johnson Jr., W.D. in Principles and Practice of Infectious Diseases, 4th ed. (eds. Mandell, G.L., Bennett, J.E. & Dolin, R.) 2141– 2143 (Churchill Livingstone, New York, 1994).

    Google Scholar 

  2. Bryceson, A.D. Clinical pathology of the Jarisch-Herxheimer reaction. J. Infect. Dis. 133, 696–704 (1976).

    Article  CAS  Google Scholar 

  3. Luger, S.W. et al. Comparison of cefuroxime axetil and doxycycline in treatment of patients with early Lyme disease associated with erythema migrans. Antimicrob. Agents Chemother. 39, 661– 667 (1995).

    Article  CAS  Google Scholar 

  4. Wright, D.J. Reaction following treatment of murine borreliosis and Shwartzman type reacion with borrelial sonicates. Parasite Immunol. 2, 201–221 (1980).

    Article  CAS  Google Scholar 

  5. Negussie, Y. et al. Detection of plasma tumor necrosis factor, interleukins 6, and 8 during the Jarisch-Herxheimer Reaction of relapsing fever. J. Exp. Med. 175, 1207–1212 (1992).

    Article  CAS  Google Scholar 

  6. Fekade, D. et al. Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha. N. Engl. J. Med. 335, 311–315 (1996).

    Article  CAS  Google Scholar 

  7. Takayama, K., Rothenberg, R.J. & Barbour, A.G. Absence of lipopolysaccharide in the Lyme disease spirochete, Borrelia burgdorferi. Infect. Immun. 55, 2311–2313 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Radolf, J.D. et al. Lipoproteins of Borrelia burgdorferi and Treponema pallidum activate cachectin/tumor necrosis factor synthesis. Analysis using a CAT reporter construct. J. Immunol. 147, 1968– 1974 (1991).

    CAS  PubMed  Google Scholar 

  9. Weis, J.J., Ma, Y. & Erdile, L.F. Biological activities of native and recombinant Borrelia burgdorferi outer surface protein A: dependence on lipid modification. Infect. Immun. 62, 4632–4636 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bouchon, B., Klein, M., Bischoff, R., Van Dorsselaer, A. & Roitsch, C. Analysis of the lipidated recombinant outer surface protein A from Borrelia burgdorferi by mass spectrometry. Anal. Biochem. 246, 52–61 (1997).

    Article  CAS  Google Scholar 

  11. Braun, V. Covalent lipoprotein from the outer membrane of Escherichia coli. Biochim. Biophys. Acta 415, 335–377 (1975).

    Article  CAS  Google Scholar 

  12. Fraser, C.M. et al. Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature 390, 580–586 (1997).

    Article  CAS  Google Scholar 

  13. Cutler, S.J. et al. Borrelia recurrentis characterization and comparison with relapsing-fever, Lyme-associated, and other Borrelia spp. Int. J. Syst. Bacteriol. 47, 958–968 (1997).

    Article  CAS  Google Scholar 

  14. Cutler, S.J. et al. Successful in-vitro cultivation of Borrelia recurrentis. Lancet 343,–242 (1994).

    PubMed  Google Scholar 

  15. de Silva, A.M.D. & Fikrig, E. Borrelia burgdorferi genes selectively expressed in ticks and mammals. Parasitol. Today 13, 267–270 (1997).

    Article  CAS  Google Scholar 

  16. de Silva, A.M.D. & Fikrig, E. Arthropod- and host-specific gene expression by Borrelia burgdorferi. J. Clin. Invest. 99, 377–379 (1997).

    Article  CAS  Google Scholar 

  17. Schwan, T.G., Piesman, J., Golde, W.T., Dolan, M.C. & Rosa, P.A. Induction of an outer surface protein on Borrelia burgdorferi during tick feeding. Proc. Natl. Acad. Sci. USA 92, 2909–2913 (1995).

    Article  CAS  Google Scholar 

  18. Montgomery, R.R., Malawista, S.E., Feen, K.J. & Bockenstedt, L.K. Direct demonstration of antigenic substitution of Borrelia burgdorferi ex vivo: exploration of the paradox of the early immune response to outer surface proteins A and C in Lyme disease. J. Exp. Med. 183, 261–269 (1996).

    Article  CAS  Google Scholar 

  19. Barbour, A.G., Tessier, S.L. & Stoenner, H.G. Variable major proteins of Borrellia hermsii. J. Exp. Med. 156, 1312–1324 (1982).

    Article  CAS  Google Scholar 

  20. Plasterk, R.H., Simon, M.I. & Barbour, A.G. Transposition of structural genes to an expression sequence on a linear plasmid causes antigenic variation in the bacterium Borrelia hermsii. Nature 318, 257– 263 (1985).

    Article  CAS  Google Scholar 

  21. Barbour, A.G. Antigenic variation of a relapsing fever Borrelia species. Annu. Rev. Microbiol. 44, 155–171 (1990).

    Article  CAS  Google Scholar 

  22. Cadavid, D., Thomas, D.D., Crawley, R. & Barbour, A.G. Variability of a bacterial surface protein and disease expression in a possible mouse model of systemic Lyme borreliosis. J. Exp. Med. 179, 631–642 (1994).

    Article  CAS  Google Scholar 

  23. Zhang, J.R., Hardham, J.M., Barbour, A.G. & Norris, S.J. Antigenic variation in Lyme disease borreliae by promiscuous recombination of VMP-like sequence cassettes. Cell 89, 275–285 (1997).

    Article  CAS  Google Scholar 

  24. Pradines Figueres, A. & Raetz, C.R. Processing and secretion of tumor necrosis factor alpha in endotoxin-treated Mono Mac 6 cells are dependent on phorbol myristate acetate. J. Biol. Chem. 267, 23261–23268 (1992).

    CAS  PubMed  Google Scholar 

  25. Allan, R.J., Rowe, A. & Kwiatkowski, D. Plasmodium falciparum varies in its ability to induce tumor necrosis factor. Infect. Immun. 61, 4772–4776 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Matsudaira, P. in A Practical Guide to Protein Purification for Microsequencing (Academic Press, London, 1993).

    Google Scholar 

  27. Barbour, A.G. & Garon, C.F. Linear plasmids of the bacterium Borrelia burgdorferi have covalently closed ends. Science 237, 409–411 (1987).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank L. Barber for peptide sequencing. This work was funded by the Medical Research Council, UK.

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Vidal, V., Scragg, I., Cutler, S. et al. Variable major lipoprotein is a principal TNF-inducing factor of louse-borne relapsing fever. Nat Med 4, 1416–1420 (1998). https://doi.org/10.1038/4007

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