Skip to main content
PMC home page
Infection and Immunity logoLink to Infection and Immunity
. 1997 Aug;65(8):3100–3106. doi: 10.1128/iai.65.8.3100-3106.1997

Effects of Ixodes scapularis and Borrelia burgdorferi on modulation of the host immune response: induction of a TH2 cytokine response in Lyme disease-susceptible (C3H/HeJ) mice but not in disease-resistant (BALB/c) mice.

N Zeidner 1, M L Mbow 1, M Dolan 1, R Massung 1, E Baca 1, J Piesman 1
PMCID: PMC175437  PMID: 9234760

Abstract

Previous studies have demonstrated that both Ixodes scapularis saliva and Borrelia burgdorferi antigens modulated lymphokines and monokines in vitro. The studies presented here were designed to delineate the role of I. scapularis and B. burgdorferi in modulation of the host immune response in vivo. Infestation of C3H/HeJ mice with infected I. scapularis resulted in an up regulation of IL-4 as early as 8 days after tick infestation, while the levels of T helper cell type 1 (TH1) cytokines, interleukin-2 (IL-2) and gamma interferon (IFN-gamma), were significantly decreased by days 10 to 12. In contrast, the cytokine profile of BALB/c mice exposed to infected nymphal ticks resulted in only transient alterations in IL-4, IL-2, and IFN-gamma production throughout a 12-day period postinfestation. Although the IL-10 level was elevated in both C3H/HeJ and BALB/c mice infested with infected nymphal ticks, no significant difference in the levels of IL-10 was noted between the mouse strains. Flow-cytometric analysis demonstrated increases in the numbers of splenic B-cell and CD4+ lymphocytes in C3H/HeJ but not BALB/c mice exposed to infected ticks. Cell depletion experiments with C3H/HeJ mice demonstrated that CD4+ cells were the sole producers of IFN-gamma and IL-10 while both CD4+ and CD8+ splenocytes contributed to the production of IL-2 and IL-4. These findings suggest that B and CD4+ splenocytes are activated, increase in number, and produce a polarized TH2 response in C3H/HeJ mice exposed to infected I. scapularis. Given that C3H/HeJ mice are susceptible to Lyme disease and the initial TH2 polarization is not evident in BALB/c mice, effective control of this response may have ramifications for spirochete transmission in vivo.

Full Text

The Full Text of this article is available as a PDF (163.9 KB).

Selected References

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

  1. Barthold S. W. Infectivity of Borrelia burgdorferi relative to route of inoculation and genotype in laboratory mice. J Infect Dis. 1991 Feb;163(2):419–420. doi: 10.1093/infdis/163.2.419. [DOI] [PubMed] [Google Scholar]
  2. Burkot T. R., Piesman J., Wirtz R. A. Quantitation of the Borrelia burgdorferi outer surface protein A in Ixodes scapularis: fluctuations during the tick life cycle, doubling times, and loss while feeding. J Infect Dis. 1994 Oct;170(4):883–889. doi: 10.1093/infdis/170.4.883. [DOI] [PubMed] [Google Scholar]
  3. Busch D. H., Jassoy C., Brinckmann U., Girschick H., Huppertz H. I. Detection of Borrelia burgdorferi-specific CD8+ cytotoxic T cells in patients with Lyme arthritis. J Immunol. 1996 Oct 15;157(8):3534–3541. [PubMed] [Google Scholar]
  4. Fikrig E., Barthold S. W., Chen M., Grewal I. S., Craft J., Flavell R. A. Protective antibodies in murine Lyme disease arise independently of CD40 ligand. J Immunol. 1996 Jul 1;157(1):1–3. [PubMed] [Google Scholar]
  5. Fikrig E., Tao H., Chen M., Barthold S. W., Flavell R. A. Lyme borreliosis in transgenic mice tolerant to Borrelia burgdorferi OspA or B. J Clin Invest. 1995 Oct;96(4):1706–1714. doi: 10.1172/JCI118215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Filgueira L., Nestlé F. O., Rittig M., Joller H. I., Groscurth P. Human dendritic cells phagocytose and process Borrelia burgdorferi. J Immunol. 1996 Oct 1;157(7):2998–3005. [PubMed] [Google Scholar]
  7. Ganapamo F., Rutti B., Brossard M. Immunosuppression and cytokine production in mice infested with Ixodes ricinus ticks: a possible role of laminin and interleukin-10 on the in vitro responsiveness of lymphocytes to mitogens. Immunology. 1996 Feb;87(2):259–263. doi: 10.1046/j.1365-2567.1996.450512.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ganapamo F., Rutti B., Brossard M. In vitro production of interleukin-4 and interferon-gamma by lymph node cells from BALB/c mice infested with nymphal Ixodes ricinus ticks. Immunology. 1995 May;85(1):120–124. [PMC free article] [PubMed] [Google Scholar]
  9. Karupiah G., Xie Q. W., Buller R. M., Nathan C., Duarte C., MacMicking J. D. Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science. 1993 Sep 10;261(5127):1445–1448. doi: 10.1126/science.7690156. [DOI] [PubMed] [Google Scholar]
  10. Keane-Myers A., Maliszewski C. R., Finkelman F. D., Nickell S. P. Recombinant IL-4 treatment augments resistance to Borrelia burgdorferi infections in both normal susceptible and antibody-deficient susceptible mice. J Immunol. 1996 Apr 1;156(7):2488–2494. [PubMed] [Google Scholar]
  11. Keane-Myers A., Nickell S. P. Role of IL-4 and IFN-gamma in modulation of immunity to Borrelia burgdorferi in mice. J Immunol. 1995 Aug 15;155(4):2020–2028. [PubMed] [Google Scholar]
  12. Ma Y., Seiler K. P., Tai K. F., Yang L., Woods M., Weis J. J. Outer surface lipoproteins of Borrelia burgdorferi stimulate nitric oxide production by the cytokine-inducible pathway. Infect Immun. 1994 Sep;62(9):3663–3671. doi: 10.1128/iai.62.9.3663-3671.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Peterson P. K., Clawson C. C., Lee D. A., Garlich D. J., Quie P. G., Johnson R. C. Human phagocyte interactions with the Lyme disease spirochete. Infect Immun. 1984 Nov;46(2):608–611. doi: 10.1128/iai.46.2.608-611.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Piesman J. Standard system for infecting ticks (Acari: Ixodidae) with the Lyme disease spirochete, Borrelia burgdorferi. J Med Entomol. 1993 Jan;30(1):199–203. doi: 10.1093/jmedent/30.1.199. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Ramachandra R. N., Wikel S. K. Effects of Dermacentor andersoni (Acari: Ixodidae) salivary gland extracts on Bos indicus and B. taurus lymphocytes and macrophages: in vitro cytokine elaboration and lymphocyte blastogenesis. J Med Entomol. 1995 May;32(3):338–345. doi: 10.1093/jmedent/32.3.338. [DOI] [PubMed] [Google Scholar]
  17. Ramachandra R. N., Wikel S. K. Modulation of host-immune responses by ticks (Acari: Ixodidae): effect of salivary gland extracts on host macrophages and lymphocyte cytokine production. J Med Entomol. 1992 Sep;29(5):818–826. doi: 10.1093/jmedent/29.5.818. [DOI] [PubMed] [Google Scholar]
  18. Rao T. D., Frey A. B. Protective resistance to experimental Borrelia burgdorferi infection of mice by adoptive transfer of a CD4+ T cell clone. Cell Immunol. 1995 May;162(2):225–234. doi: 10.1006/cimm.1995.1073. [DOI] [PubMed] [Google Scholar]
  19. Ribeiro J. M. How ticks make a living. Parasitol Today. 1995 Mar;11(3):91–93. doi: 10.1016/0169-4758(95)80162-6. [DOI] [PubMed] [Google Scholar]
  20. Ribeiro J. M., Makoul G. T., Levine J., Robinson D. R., Spielman A. Antihemostatic, antiinflammatory, and immunosuppressive properties of the saliva of a tick, Ixodes dammini. J Exp Med. 1985 Feb 1;161(2):332–344. doi: 10.1084/jem.161.2.332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Roehrig J. T., Piesman J., Hunt A. R., Keen M. G., Happ C. M., Johnson B. J. The hamster immune response to tick-transmitted Borrelia burgdorferi differs from the response to needle-inoculated, cultured organisms. J Immunol. 1992 Dec 1;149(11):3648–3653. [PubMed] [Google Scholar]
  22. 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 U S A. 1995 Mar 28;92(7):2909–2913. doi: 10.1073/pnas.92.7.2909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Shih C. M., Pollack R. J., Telford S. R., 3rd, Spielman A. Delayed dissemination of Lyme disease spirochetes from the site of deposition in the skin of mice. J Infect Dis. 1992 Oct;166(4):827–831. doi: 10.1093/infdis/166.4.827. [DOI] [PubMed] [Google Scholar]
  24. Shih C. M., Telford S. R., 3rd, Pollack R. J., Spielman A. Rapid dissemination by the agent of Lyme disease in hosts that permit fulminating infection. Infect Immun. 1993 Jun;61(6):2396–2399. doi: 10.1128/iai.61.6.2396-2399.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Steere A. C. Lyme disease. N Engl J Med. 1989 Aug 31;321(9):586–596. doi: 10.1056/NEJM198908313210906. [DOI] [PubMed] [Google Scholar]
  26. Urioste S., Hall L. R., Telford S. R., 3rd, Titus R. G. Saliva of the Lyme disease vector, Ixodes dammini, blocks cell activation by a nonprostaglandin E2-dependent mechanism. J Exp Med. 1994 Sep 1;180(3):1077–1085. doi: 10.1084/jem.180.3.1077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Yang L., Ma Y., Schoenfeld R., Griffiths M., Eichwald E., Araneo B., Weis J. J. Evidence for B-lymphocyte mitogen activity in Borrelia burgdorferi-infected mice. Infect Immun. 1992 Aug;60(8):3033–3041. doi: 10.1128/iai.60.8.3033-3041.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Yang L., Weis J. H., Eichwald E., Kolbert C. P., Persing D. H., Weis J. J. Heritable susceptibility to severe Borrelia burgdorferi-induced arthritis is dominant and is associated with persistence of large numbers of spirochetes in tissues. Infect Immun. 1994 Feb;62(2):492–500. doi: 10.1128/iai.62.2.492-500.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Zeidner N., Dreitz M., Belasco D., Fish D. Suppression of acute Ixodes scapularis-induced Borrelia burgdorferi infection using tumor necrosis factor-alpha, interleukin-2, and interferon-gamma. J Infect Dis. 1996 Jan;173(1):187–195. doi: 10.1093/infdis/173.1.187. [DOI] [PubMed] [Google Scholar]
  31. de Silva A. M., Telford S. R., 3rd, Brunet L. R., Barthold S. W., Fikrig E. Borrelia burgdorferi OspA is an arthropod-specific transmission-blocking Lyme disease vaccine. J Exp Med. 1996 Jan 1;183(1):271–275. doi: 10.1084/jem.183.1.271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. de Souza M. S., Smith A. L., Beck D. S., Terwilliger G. A., Fikrig E., Barthold S. W. Long-term study of cell-mediated responses to Borrelia burgdorferi in the laboratory mouse. Infect Immun. 1993 May;61(5):1814–1822. doi: 10.1128/iai.61.5.1814-1822.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES