Skip to main content
PMC home page
Infection and Immunity logoLink to Infection and Immunity
. 1996 Oct;64(10):4307–4312. doi: 10.1128/iai.64.10.4307-4312.1996

Borrelia burgdorferi induces secretion of pro-urokinase-type plasminogen activator by human monocytes.

H Fuchs 1, M M Simon 1, R Wallich 1, M Bechtel 1, M D Kramer 1
PMCID: PMC174371  PMID: 8926103

Abstract

Borrelia burgdorferi is transmitted by infected ticks and causes Lyme disease. To infect distant organ sites, B. burgdorferi spirochetes must disseminate from the site of the tick bite. During dissemination from the dermal tissue, they breach tissue barriers, probably by proteolysis. The previous findings that spirochetes bind serum-derived plasminogen and that plasmin favors spirochetal invasiveness and infectivity suggested a role for plasmin in the pathogenicity of B. burgdorferi. Binding of plasminogen to spirochetes and activation into plasmin is favored in a microenvironment that is rich in plasminogen and plasminogen activators. Plasminogen is abundant in plasma and interstitial fluids, and it is increased in inflammatory exudates. Since B. burgdorferi does not express endogenous plasminogen activators, the conversion of spirochete-bound plasminogen depends on host-derived plasminogen activators. In this report, we show that both intact B. burgdorferi organisms and its recombinant outer surface lipoprotein A induce human monocytes to express and secrete urokinase-type plasminogen activator in its zymogen form (pro-uPA). Moreover, we demonstrate that the presence of B. burgdorferi accelerates the interaction between (pro-)uPA and plasmin(ogen), leading to spirochete-bound plasmin. In a pro-uPA-serum mixture, spirochete-bound plasmin activity is generated. Taken together, the data suggest that B. burgdorferi may induce pro-uPA in a monocyte-containing inflammatory site and that the spirochetal surface provides an appropriate milieu for subsequent interactions between (pro-)uPA and plasmin(ogen), which result in spirochete-bound plasmin even in the presence of inhibitors for plasminogen activators and plasmin.

Full Text

The Full Text of this article is available as a PDF (221.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andreasen P. A., Georg B., Lund L. R., Riccio A., Stacey S. N. Plasminogen activator inhibitors: hormonally regulated serpins. Mol Cell Endocrinol. 1990 Jan 2;68(1):1–19. doi: 10.1016/0303-7207(90)90164-4. [DOI] [PubMed] [Google Scholar]
  2. Blasi F., Vassalli J. D., Danø K. Urokinase-type plasminogen activator: proenzyme, receptor, and inhibitors. J Cell Biol. 1987 Apr;104(4):801–804. doi: 10.1083/jcb.104.4.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Broder C. C., Lottenberg R., von Mering G. O., Johnston K. H., Boyle M. D. Isolation of a prokaryotic plasmin receptor. Relationship to a plasminogen activator produced by the same micro-organism. J Biol Chem. 1991 Mar 15;266(8):4922–4928. [PubMed] [Google Scholar]
  4. Brower M. S., Harpel P. C. Proteolytic cleavage and inactivation of alpha 2-plasmin inhibitor and C1 inactivator by human polymorphonuclear leukocyte elastase. J Biol Chem. 1982 Aug 25;257(16):9849–9854. [PubMed] [Google Scholar]
  5. Buessecker F., Reinartz J., Schirmer U., Kramer M. D. Enzyme-linked immunosorbent assays for plasminogen activators. J Immunol Methods. 1993 Jun 18;162(2):193–200. doi: 10.1016/0022-1759(93)90384-j. [DOI] [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Coleman J. L., Sellati T. J., Testa J. E., Kew R. R., Furie M. B., Benach J. L. Borrelia burgdorferi binds plasminogen, resulting in enhanced penetration of endothelial monolayers. Infect Immun. 1995 Jul;63(7):2478–2484. doi: 10.1128/iai.63.7.2478-2484.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Danø K., Andreasen P. A., Grøndahl-Hansen J., Kristensen P., Nielsen L. S., Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139–266. doi: 10.1016/s0065-230x(08)60028-7. [DOI] [PubMed] [Google Scholar]
  9. Fuchs H., Wallich R., Simon M. M., Kramer M. D. The outer surface protein A of the spirochete Borrelia burgdorferi is a plasmin(ogen) receptor. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12594–12598. doi: 10.1073/pnas.91.26.12594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Galbe J. L., Guy E., Zapatero J. M., Peerschke E. I., Benach J. L. Vascular clearance of Borrelia burgdorferi in rats. Microb Pathog. 1993 Mar;14(3):187–201. doi: 10.1006/mpat.1993.1019. [DOI] [PubMed] [Google Scholar]
  11. Gyetko M. R., Shollenberger S. B., Sitrin R. G. Urokinase expression in mononuclear phagocytes: cytokine-specific modulation by interferon-gamma and tumor necrosis factor-alpha. J Leukoc Biol. 1992 Mar;51(3):256–263. doi: 10.1002/jlb.51.3.256. [DOI] [PubMed] [Google Scholar]
  12. Gyetko M. R., Wilkinson C. C., Sitrin R. G. Monocyte urokinase expression: modulation by interleukins. J Leukoc Biol. 1993 May;53(5):598–601. doi: 10.1002/jlb.53.5.598. [DOI] [PubMed] [Google Scholar]
  13. Hu L. T., Perides G., Noring R., Klempner M. S. Binding of human plasminogen to Borrelia burgdorferi. Infect Immun. 1995 Sep;63(9):3491–3496. doi: 10.1128/iai.63.9.3491-3496.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kenefick K. B., Lederer J. A., Schell R. F., Czuprynski C. J. Borrelia burgdorferi stimulates release of interleukin-1 activity from bovine peripheral blood monocytes. Infect Immun. 1992 Sep;60(9):3630–3634. doi: 10.1128/iai.60.9.3630-3634.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Klempner M. S., Noring R., Epstein M. P., McCloud B., Hu R., Limentani S. A., Rogers R. A. Binding of human plasminogen and urokinase-type plasminogen activator to the Lyme disease spirochete, Borrelia burgdorferi. J Infect Dis. 1995 May;171(5):1258–1265. doi: 10.1093/infdis/171.5.1258. [DOI] [PubMed] [Google Scholar]
  16. Kuusela P., Saksela O. Binding and activation of plasminogen at the surface of Staphylococcus aureus. Increase in affinity after conversion to the Lys form of the ligand. Eur J Biochem. 1990 Nov 13;193(3):759–765. doi: 10.1111/j.1432-1033.1990.tb19397.x. [DOI] [PubMed] [Google Scholar]
  17. Kuusela P., Ullberg M., Saksela O., Kronvall G. Tissue-type plasminogen activator-mediated activation of plasminogen on the surface of group A, C, and G streptococci. Infect Immun. 1992 Jan;60(1):196–201. doi: 10.1128/iai.60.1.196-201.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Loskutoff D. J., Edgington T. E. Synthesis of a fibrinolytic activator and inhibitor by endothelial cells. Proc Natl Acad Sci U S A. 1977 Sep;74(9):3903–3907. doi: 10.1073/pnas.74.9.3903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lottenberg R., Minning-Wenz D., Boyle M. D. Capturing host plasmin(ogen): a common mechanism for invasive pathogens? Trends Microbiol. 1994 Jan;2(1):20–24. doi: 10.1016/0966-842x(94)90340-9. [DOI] [PubMed] [Google Scholar]
  20. Lähteenmäki K., Virkola R., Pouttu R., Kuusela P., Kukkonen M., Korhonen T. K. Bacterial plasminogen receptors: in vitro evidence for a role in degradation of the mammalian extracellular matrix. Infect Immun. 1995 Sep;63(9):3659–3664. doi: 10.1128/iai.63.9.3659-3664.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Manchanda N., Schwartz B. S. Lipopolysaccharide-induced modulation of human monocyte urokinase production and activity. J Immunol. 1990 Dec 15;145(12):4174–4180. [PubMed] [Google Scholar]
  22. Manchanda N., Schwartz B. S. Single chain urokinase. Augmentation of enzymatic activity upon binding to monocytes. J Biol Chem. 1991 Aug 5;266(22):14580–14584. [PubMed] [Google Scholar]
  23. Miyashita C., Wenzel E., Heiden M. Plasminogen: a brief introduction into its biochemistry and function. Haemostasis. 1988;18 (Suppl 1):7–13. doi: 10.1159/000215824. [DOI] [PubMed] [Google Scholar]
  24. Radolf J. D., Arndt L. L., Akins D. R., Curetty L. L., Levi M. E., Shen Y., Davis L. S., Norgard M. V. Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytes/macrophages. J Immunol. 1995 Mar 15;154(6):2866–2877. [PubMed] [Google Scholar]
  25. Radolf J. D., Norgard M. V., Brandt M. E., Isaacs R. D., Thompson P. A., Beutler B. Lipoproteins of Borrelia burgdorferi and Treponema pallidum activate cachectin/tumor necrosis factor synthesis. Analysis using a CAT reporter construct. J Immunol. 1991 Sep 15;147(6):1968–1974. [PubMed] [Google Scholar]
  26. Reinartz J., Näher H., Mai H., Kramer M. D. Plasminogen activation in lesional skin of Pemphigus vulgaris type Neumann. Arch Dermatol Res. 1993;284(8):432–439. doi: 10.1007/BF00373352. [DOI] [PubMed] [Google Scholar]
  27. Schaible U. E., Kramer M. D., Justus C. W., Museteanu C., Simon M. M. Demonstration of antigen-specific T cells and histopathological alterations in mice experimentally inoculated with Borrelia burgdorferi. Infect Immun. 1989 Jan;57(1):41–47. doi: 10.1128/iai.57.1.41-47.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schaible U. E., Kramer M. D., Museteanu C., Zimmer G., Mossmann H., Simon M. M. The severe combined immunodeficiency (scid) mouse. A laboratory model for the analysis of Lyme arthritis and carditis. J Exp Med. 1989 Oct 1;170(4):1427–1432. doi: 10.1084/jem.170.4.1427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Steere A. C. Lyme disease. N Engl J Med. 1989 Aug 31;321(9):586–596. doi: 10.1056/NEJM198908313210906. [DOI] [PubMed] [Google Scholar]
  30. Stief T. W., Aab A., Heimburger N. Oxidative inactivation of purified human alpha-2-antiplasmin, antithrombin III, and C1-inhibitor. Thromb Res. 1988 Mar 15;49(6):581–589. doi: 10.1016/0049-3848(88)90255-1. [DOI] [PubMed] [Google Scholar]
  31. Stief T. W., Lenz P., Becker U., Heimburger N. Determination of plasminogen activator inhibitor (PAI) capacity of human plasma in presence of oxidants: a novel principle. Thromb Res. 1988 May 15;50(4):559–573. doi: 10.1016/0049-3848(88)90204-6. [DOI] [PubMed] [Google Scholar]
  32. Wallich R., Schaible U. E., Simon M. M., Heiberger A., Kramer M. D. Cloning and sequencing of the gene encoding the outer surface protein A (OspA) of a European Borrelia burgdorferi isolate. Nucleic Acids Res. 1989 Nov 11;17(21):8864–8864. doi: 10.1093/nar/17.21.8864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wang H., Lottenberg R., Boyle M. D. A role for fibrinogen in the streptokinase-dependent acquisition of plasmin(ogen) by group A streptococci. J Infect Dis. 1995 Jan;171(1):85–92. doi: 10.1093/infdis/171.1.85. [DOI] [PubMed] [Google Scholar]
  34. Wang H., Lottenberg R., Boyle M. D. Analysis of plasmin(ogen) acquisition by clinical isolates of group A streptococci incubated in human plasma. J Infect Dis. 1994 Jan;169(1):143–149. doi: 10.1093/infdis/169.1.143. [DOI] [PubMed] [Google Scholar]
  35. 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. 1994 Oct;62(10):4632–4636. doi: 10.1128/iai.62.10.4632-4636.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wheeler C. M., Coleman J. L., Habicht G. S., Benach J. L. Adult Ixodes dammini on rabbits: development of acute inflammation in the skin and immune responses to salivary gland, midgut, and spirochetal components. J Infect Dis. 1989 Feb;159(2):265–273. doi: 10.1093/infdis/159.2.265. [DOI] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES