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. 1994 Feb;62(2):492–500. doi: 10.1128/iai.62.2.492-500.1994

Heritable susceptibility to severe Borrelia burgdorferi-induced arthritis is dominant and is associated with persistence of large numbers of spirochetes in tissues.

L Yang 1, J H Weis 1, E Eichwald 1, C P Kolbert 1, D H Persing 1, J J Weis 1
PMCID: PMC186134  PMID: 8300208

Abstract

In human Lyme disease, symptoms with widely varying levels of severity have been observed. A mouse model of Lyme disease has been developed which allows analysis of mice with mild, moderate, and severe pathologies after inoculation with the spirochete Borrelia burgdorferi. To determine whether the differences in symptoms reflect differences in the number of spirochetes persisting in affected tissues, a sensitive PCR technique was developed to detect B. burgdorferi DNA in virtually any tissue of an infected mouse. This analysis, which detects DNA from as few as three spirochetes, revealed the presence of B. burgdorferi DNA in many tissues from severely arthritic C3H/HeJ mice as early as 1 week postinfection. The heart, ear, and ankle were particularly heavily infected, although B. burgdorferi DNA was also detected in spleen, liver, brain, kidney, bladder, uterus, and lymph nodes. In contrast, much lower levels of spirochete DNA were detected in tissues of infected BALB/c mice, which develop less severe arthritis when infected with B. burgdorferi than do C3H/HeJ mice. This difference was evident throughout the 5-week analysis. A competitive PCR method allowed determination of the absolute number of spirochete gene sequences in infected tissues. Ankles and hearts from C3H/HeJ mice were found to harbor 10(7) copies of the B. burgdorferi ospA gene, while these tissues from BALB/c mice contained 5- and 10-fold less B. burgdorferi DNA, respectively. The genetic regulation of severe pathology was analyzed by infecting the offspring of a cross between C3H/HeJ and BALB/c mice. The F1 mice developed severe arthritis and contained high levels of Borrelia DNA in the heart and ankle, similar to the C3H/HeJ parent. These findings indicate that susceptibility to severe arthritis is a dominant trait and suggest that it may correlate with high levels of persisting spirochetes. Models of pathology in Lyme disease should take into consideration the fact that severity of pathology may be directly related to the number of organisms in infected tissues.

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Selected References

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

  1. Armstrong A. L., Barthold S. W., Persing D. H., Beck D. S. Carditis in Lyme disease susceptible and resistant strains of laboratory mice infected with Borrelia burgdorferi. Am J Trop Med Hyg. 1992 Aug;47(2):249–258. doi: 10.4269/ajtmh.1992.47.249. [DOI] [PubMed] [Google Scholar]
  2. Barbour A. G. Isolation and cultivation of Lyme disease spirochetes. Yale J Biol Med. 1984 Jul-Aug;57(4):521–525. [PMC free article] [PubMed] [Google Scholar]
  3. Barthold S. W., Beck D. S., Hansen G. M., Terwilliger G. A., Moody K. D. Lyme borreliosis in selected strains and ages of laboratory mice. J Infect Dis. 1990 Jul;162(1):133–138. doi: 10.1093/infdis/162.1.133. [DOI] [PubMed] [Google Scholar]
  4. Barthold S. W., Persing D. H., Armstrong A. L., Peeples R. A. Kinetics of Borrelia burgdorferi dissemination and evolution of disease after intradermal inoculation of mice. Am J Pathol. 1991 Aug;139(2):263–273. [PMC free article] [PubMed] [Google Scholar]
  5. Barthold S. W., Sidman C. L., Smith A. L. Lyme borreliosis in genetically resistant and susceptible mice with severe combined immunodeficiency. Am J Trop Med Hyg. 1992 Nov;47(5):605–613. doi: 10.4269/ajtmh.1992.47.605. [DOI] [PubMed] [Google Scholar]
  6. Beck G., Benach J. L., Habicht G. S. Isolation of interleukin 1 from joint fluids of patients with Lyme disease. J Rheumatol. 1989 Jun;16(6):800–806. [PubMed] [Google Scholar]
  7. Bergström S., Bundoc V. G., Barbour A. G. Molecular analysis of linear plasmid-encoded major surface proteins, OspA and OspB, of the Lyme disease spirochaete Borrelia burgdorferi. Mol Microbiol. 1989 Apr;3(4):479–486. doi: 10.1111/j.1365-2958.1989.tb00194.x. [DOI] [PubMed] [Google Scholar]
  8. Defosse D. L., Johnson R. C. In vitro and in vivo induction of tumor necrosis factor alpha by Borrelia burgdorferi. Infect Immun. 1992 Mar;60(3):1109–1113. doi: 10.1128/iai.60.3.1109-1113.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gassmann G. S., Kramer M., Göbel U. B., Wallich R. Nucleotide sequence of a gene encoding the Borrelia burgdorferi flagellin. Nucleic Acids Res. 1989 May 11;17(9):3590–3590. doi: 10.1093/nar/17.9.3590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gern L., Schaible U. E., Simon M. M. Mode of inoculation of the Lyme disease agent Borrelia burgdorferi influences infection and immune responses in inbred strains of mice. J Infect Dis. 1993 Apr;167(4):971–975. doi: 10.1093/infdis/167.4.971. [DOI] [PubMed] [Google Scholar]
  11. Hinnebusch J., Barbour A. G. Linear- and circular-plasmid copy numbers in Borrelia burgdorferi. J Bacteriol. 1992 Aug;174(16):5251–5257. doi: 10.1128/jb.174.16.5251-5257.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kalish R. A., Leong J. M., Steere A. C. Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi. Infect Immun. 1993 Jul;61(7):2774–2779. doi: 10.1128/iai.61.7.2774-2779.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Keffer J., Probert L., Cazlaris H., Georgopoulos S., Kaslaris E., Kioussis D., Kollias G. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991 Dec;10(13):4025–4031. doi: 10.1002/j.1460-2075.1991.tb04978.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kitten T., Barbour A. G. The relapsing fever agent Borrelia hermsii has multiple copies of its chromosome and linear plasmids. Genetics. 1992 Oct;132(2):311–324. doi: 10.1093/genetics/132.2.311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ma Y., Sturrock A., Weis J. J. Intracellular localization of Borrelia burgdorferi within human endothelial cells. Infect Immun. 1991 Feb;59(2):671–678. doi: 10.1128/iai.59.2.671-678.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mann K., Deutzmann R., Aumailley M., Timpl R., Raimondi L., Yamada Y., Pan T. C., Conway D., Chu M. L. Amino acid sequence of mouse nidogen, a multidomain basement membrane protein with binding activity for laminin, collagen IV and cells. EMBO J. 1989 Jan;8(1):65–72. doi: 10.1002/j.1460-2075.1989.tb03349.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mason D. Genetic variation in the stress response: susceptibility to experimental allergic encephalomyelitis and implications for human inflammatory disease. Immunol Today. 1991 Feb;12(2):57–60. doi: 10.1016/0167-5699(91)90158-P. [DOI] [PubMed] [Google Scholar]
  18. Miller L. C., Lynch E. A., Isa S., Logan J. W., Dinarello C. A., Steere A. C. Balance of synovial fluid IL-1 beta and IL-1 receptor antagonist and recovery from Lyme arthritis. Lancet. 1993 Jan 16;341(8838):146–148. doi: 10.1016/0140-6736(93)90006-3. [DOI] [PubMed] [Google Scholar]
  19. Pachner A. R., Delaney E., Ricalton N. S. Murine Lyme borreliosis: route of inoculation determines immune response and infectivity. Reg Immunol. 1992 Nov-Dec;4(6):345–351. [PubMed] [Google Scholar]
  20. Persing D. H., Telford S. R., 3rd, Spielman A., Barthold S. W. Detection of Borrelia burgdorferi infection in Ixodes dammini ticks with the polymerase chain reaction. J Clin Microbiol. 1990 Mar;28(3):566–572. doi: 10.1128/jcm.28.3.566-572.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Piatak M., Jr, Luk K. C., Williams B., Lifson J. D. Quantitative competitive polymerase chain reaction for accurate quantitation of HIV DNA and RNA species. Biotechniques. 1993 Jan;14(1):70–81. [PubMed] [Google Scholar]
  22. Picken R. N. Polymerase chain reaction primers and probes derived from flagellin gene sequences for specific detection of the agents of Lyme disease and North American relapsing fever. J Clin Microbiol. 1992 Jan;30(1):99–114. doi: 10.1128/jcm.30.1.99-114.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. 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]
  25. Ryan J. L., Glode L. M., Rosenstreich D. L. Lack of responsiveness of C3H/HeJ macrophages to lipopolysaccharide: the cellular basis of LPS-stimulated metabolism. J Immunol. 1979 Mar;122(3):932–935. [PubMed] [Google Scholar]
  26. Schaible U. E., Gay S., Museteanu C., Kramer M. D., Zimmer G., Eichmann K., Museteanu U., Simon M. M. Lyme borreliosis in the severe combined immunodeficiency (scid) mouse manifests predominantly in the joints, heart, and liver. Am J Pathol. 1990 Oct;137(4):811–820. [PMC free article] [PubMed] [Google Scholar]
  27. Schoenfeld R., Araneo B., Ma Y., Yang L. M., Weis J. J. Demonstration of a B-lymphocyte mitogen produced by the Lyme disease pathogen, Borrelia burgdorferi. Infect Immun. 1992 Feb;60(2):455–464. doi: 10.1128/iai.60.2.455-464.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sigal L. H. Lyme disease, 1988: immunologic manifestations and possible immunopathogenetic mechanisms. Semin Arthritis Rheum. 1989 Feb;18(3):151–167. doi: 10.1016/0049-0172(89)90058-9. [DOI] [PubMed] [Google Scholar]
  29. Sigal L. H., Steere A. C., Dwyer J. M. In vivo and in vitro evidence of B cell hyperactivity during Lyme disease. J Rheumatol. 1988 Apr;15(4):648–654. [PubMed] [Google Scholar]
  30. Steere A. C. Lyme disease. N Engl J Med. 1989 Aug 31;321(9):586–596. doi: 10.1056/NEJM198908313210906. [DOI] [PubMed] [Google Scholar]
  31. Tan S. S., Weis J. H. Development of a sensitive reverse transcriptase PCR assay, RT-RPCR, utilizing rapid cycle times. PCR Methods Appl. 1992 Nov;2(2):137–143. doi: 10.1101/gr.2.2.137. [DOI] [PubMed] [Google Scholar]
  32. Whitmire W. M., Garon C. F. Specific and nonspecific responses of murine B cells to membrane blebs of Borrelia burgdorferi. Infect Immun. 1993 Apr;61(4):1460–1467. doi: 10.1128/iai.61.4.1460-1467.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. 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]
  34. de Koning J., Hoogkamp-Korstanje J. A., van der Linde M. R., Crijns H. J. Demonstration of spirochetes in cardiac biopsies of patients with Lyme disease. J Infect Dis. 1989 Jul;160(1):150–153. doi: 10.1093/infdis/160.1.150. [DOI] [PubMed] [Google Scholar]
  35. de Souza M. S., Fikrig E., Smith A. L., Flavell R. A., Barthold S. W. Nonspecific proliferative responses of murine lymphocytes to Borrelia burgdorferi antigens. J Infect Dis. 1992 Mar;165(3):471–478. doi: 10.1093/infdis/165.3.471. [DOI] [PubMed] [Google Scholar]

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