Skip to main content
NCBI home page
Genetics logoLink to Genetics
. 1999 Jan;151(1):15–30. doi: 10.1093/genetics/151.1.15

Genetic diversity of ospC in a local population of Borrelia burgdorferi sensu stricto.

I N Wang 1, D E Dykhuizen 1, W Qiu 1, J J Dunn 1, E M Bosler 1, B J Luft 1
PMCID: PMC1460459  PMID: 9872945

Abstract

The outer surface protein, OspC, is highly variable in Borrelia burgdorferi sensu stricto, the agent of Lyme disease. We have shown that even within a single population OspC is highly variable. The variation of ospA and ospC in the 40 infected deer ticks collected from a single site on Shelter Island, New York, was determined using PCR-SSCP. There is very strong apparent linkage disequilibrium between ospA and ospC alleles, even though they are located on separate plasmids. Thirteen discernible SSCP mobility classes for ospC were identified and the DNA sequence for each was determined. These sequences, combined with 40 GenBank sequences, allow us to define 19 major ospC groups. Sequences within a major ospC group are, on average, <1% different from each other, while sequences between major ospC groups are, on average, approximately 20% different. The tick sample contains 11 major ospC groups, GenBank contains 16 groups, with 8 groups found in both samples. Thus, the ospC variation within a local population is almost as great as the variation of a similar-sized sample of the entire species. The Ewens-Watterson-Slatkin test of allele frequency showed significant deviation from the neutral expectation, indicating balancing selection for these major ospC groups. The variation represented by major ospC groups needs to be considered if the OspC protein is to be used as a serodiagnostic antigen or a vaccine.

Full Text

The Full Text of this article is available as a PDF (303.7 KB).

Selected References

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

  1. Aguadé M., Meyers W., Long A. D., Langley C. H. Single-strand conformation polymorphism analysis coupled with stratified DNA sequencing reveals reduced sequence variation in the su(s) and su(wa) regions of the Drosophila melanogaster X chromosome. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4658–4662. doi: 10.1073/pnas.91.11.4658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anthonissen F. M., De Kesel M., Hoet P. P., Bigaignon G. H. Evidence for the involvement of different genospecies of Borrelia in the clinical outcome of Lyme disease in Belgium. Res Microbiol. 1994 May;145(4):327–331. doi: 10.1016/0923-2508(94)90187-2. [DOI] [PubMed] [Google Scholar]
  3. Assous M. V., Postic D., Paul G., Névot P., Baranton G. Western blot analysis of sera from Lyme borreliosis patients according to the genomic species of the Borrelia strains used as antigens. Eur J Clin Microbiol Infect Dis. 1993 Apr;12(4):261–268. doi: 10.1007/BF01967256. [DOI] [PubMed] [Google Scholar]
  4. Balmelli T., Piffaretti J. C. Analysis of the genetic polymorphism of Borrelia burgdorferi sensu lato by multilocus enzyme electrophoresis. Int J Syst Bacteriol. 1996 Jan;46(1):167–172. doi: 10.1099/00207713-46-1-167. [DOI] [PubMed] [Google Scholar]
  5. Balmelli T., Piffaretti J. C. Association between different clinical manifestations of Lyme disease and different species of Borrelia burgdorferi sensu lato. Res Microbiol. 1995 May;146(4):329–340. doi: 10.1016/0923-2508(96)81056-4. [DOI] [PubMed] [Google Scholar]
  6. Baranton G., Postic D., Saint Girons I., Boerlin P., Piffaretti J. C., Assous M., Grimont P. A. Delineation of Borrelia burgdorferi sensu stricto, Borrelia garinii sp. nov., and group VS461 associated with Lyme borreliosis. Int J Syst Bacteriol. 1992 Jul;42(3):378–383. doi: 10.1099/00207713-42-3-378. [DOI] [PubMed] [Google Scholar]
  7. Barbour A. G., Fish D. The biological and social phenomenon of Lyme disease. Science. 1993 Jun 11;260(5114):1610–1616. doi: 10.1126/science.8503006. [DOI] [PubMed] [Google Scholar]
  8. Barbour A. G., Garon C. F. The genes encoding major surface proteins of Borrelia burgdorferi are located on a plasmid. Ann N Y Acad Sci. 1988;539:144–153. doi: 10.1111/j.1749-6632.1988.tb31847.x. [DOI] [PubMed] [Google Scholar]
  9. Barthold S. W., de Souza M. S., Janotka J. L., Smith A. L., Persing D. H. Chronic Lyme borreliosis in the laboratory mouse. Am J Pathol. 1993 Sep;143(3):959–971. [PMC free article] [PubMed] [Google Scholar]
  10. Burgdorfer W., Barbour A. G., Hayes S. F., Benach J. L., Grunwaldt E., Davis J. P. Lyme disease-a tick-borne spirochetosis? Science. 1982 Jun 18;216(4552):1317–1319. doi: 10.1126/science.7043737. [DOI] [PubMed] [Google Scholar]
  11. Caporale D. A., Kocher T. D. Sequence variation in the outer-surface-protein genes of Borrelia burgdorferi. Mol Biol Evol. 1994 Jan;11(1):51–64. doi: 10.1093/oxfordjournals.molbev.a040092. [DOI] [PubMed] [Google Scholar]
  12. Craft J. E., Fischer D. K., Shimamoto G. T., Steere A. C. Antigens of Borrelia burgdorferi recognized during Lyme disease. Appearance of a new immunoglobulin M response and expansion of the immunoglobulin G response late in the illness. J Clin Invest. 1986 Oct;78(4):934–939. doi: 10.1172/JCI112683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dressler F., Whalen J. A., Reinhardt B. N., Steere A. C. Western blotting in the serodiagnosis of Lyme disease. J Infect Dis. 1993 Feb;167(2):392–400. doi: 10.1093/infdis/167.2.392. [DOI] [PubMed] [Google Scholar]
  14. Dykhuizen D. E., Polin D. S., Dunn J. J., Wilske B., Preac-Mursic V., Dattwyler R. J., Luft B. J. Borrelia burgdorferi is clonal: implications for taxonomy and vaccine development. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10163–10167. doi: 10.1073/pnas.90.21.10163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Engstrom S. M., Shoop E., Johnson R. C. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol. 1995 Feb;33(2):419–427. doi: 10.1128/jcm.33.2.419-427.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fikrig E., Barthold S. W., Persing D. H., Sun X., Kantor F. S., Flavell R. A. Borrelia burgdorferi strain 25015: characterization of outer surface protein A and vaccination against infection. J Immunol. 1992 Apr 1;148(7):2256–2260. [PubMed] [Google Scholar]
  17. Foretz M., Postic D., Baranton G. Phylogenetic analysis of Borrelia burgdorferi sensu stricto by arbitrarily primed PCR and pulsed-field gel electrophoresis. Int J Syst Bacteriol. 1997 Jan;47(1):11–18. doi: 10.1099/00207713-47-1-11. [DOI] [PubMed] [Google Scholar]
  18. Fung B. P., McHugh G. L., Leong J. M., Steere A. C. Humoral immune response to outer surface protein C of Borrelia burgdorferi in Lyme disease: role of the immunoglobulin M response in the serodiagnosis of early infection. Infect Immun. 1994 Aug;62(8):3213–3221. doi: 10.1128/iai.62.8.3213-3221.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gerber M. A., Shapiro E. D., Bell G. L., Sampieri A., Padula S. J. Recombinant outer surface protein C ELISA for the diagnosis of early Lyme disease. J Infect Dis. 1995 Mar;171(3):724–727. doi: 10.1093/infdis/171.3.724. [DOI] [PubMed] [Google Scholar]
  20. Gilmore R. D., Jr, Kappel K. J., Dolan M. C., Burkot T. R., Johnson B. J. Outer surface protein C (OspC), but not P39, is a protective immunogen against a tick-transmitted Borrelia burgdorferi challenge: evidence for a conformational protective epitope in OspC. Infect Immun. 1996 Jun;64(6):2234–2239. doi: 10.1128/iai.64.6.2234-2239.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Golde W. T., Burkot T. R., Piesman J., Dolan M. C., Capiau C., Hauser P., Dequesne G., Lobet Y. The Lyme disease vaccine candidate outer surface protein A (OspA) in a formulation compatible with human use protects mice against natural tick transmission of B. burgdorferi. Vaccine. 1995 Apr;13(5):435–441. doi: 10.1016/0264-410x(94)00027-k. [DOI] [PubMed] [Google Scholar]
  22. Guttman D. S., Wang P. W., Wang I. N., Bosler E. M., Luft B. J., Dykhuizen D. E. Multiple infections of Ixodes scapularis ticks by Borrelia burgdorferi as revealed by single-strand conformation polymorphism analysis. J Clin Microbiol. 1996 Mar;34(3):652–656. doi: 10.1128/jcm.34.3.652-656.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hofmeister E. K., Childs J. E. Analysis of Borrelia burgdorferi sequentially isolated from Peromyscus leucopus captured at a Lyme disease enzootic site. J Infect Dis. 1995 Aug;172(2):462–469. doi: 10.1093/infdis/172.2.462. [DOI] [PubMed] [Google Scholar]
  24. Hongyo T., Buzard G. S., Calvert R. J., Weghorst C. M. 'Cold SSCP': a simple, rapid and non-radioactive method for optimized single-strand conformation polymorphism analyses. Nucleic Acids Res. 1993 Aug 11;21(16):3637–3642. doi: 10.1093/nar/21.16.3637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hughes A. L., Nei M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature. 1988 Sep 8;335(6186):167–170. doi: 10.1038/335167a0. [DOI] [PubMed] [Google Scholar]
  26. Hughes C. A., Engstrom S. M., Coleman L. A., Kodner C. B., Johnson R. C. Protective immunity is induced by a Borrelia burgdorferi mutant that lacks OspA and OspB. Infect Immun. 1993 Dec;61(12):5115–5122. doi: 10.1128/iai.61.12.5115-5122.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hughes M. K., Hughes A. L. Natural selection on Plasmodium surface proteins. Mol Biochem Parasitol. 1995 Apr;71(1):99–113. doi: 10.1016/0166-6851(95)00037-2. [DOI] [PubMed] [Google Scholar]
  28. Jauris-Heipke S., Liegl G., Preac-Mursic V., Rössler D., Schwab E., Soutschek E., Will G., Wilske B. Molecular analysis of genes encoding outer surface protein C (OspC) of Borrelia burgdorferi sensu lato: relationship to ospA genotype and evidence of lateral gene exchange of ospC. J Clin Microbiol. 1995 Jul;33(7):1860–1866. doi: 10.1128/jcm.33.7.1860-1866.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jonsson M., Bergström S. Transcriptional and translational regulation of the expression of the major outer surface proteins in Lyme disease Borrelia strains. Microbiology. 1995 Jun;141(Pt 6):1321–1329. doi: 10.1099/13500872-141-6-1321. [DOI] [PubMed] [Google Scholar]
  30. Kawabata H., Masuzawa T., Yanagihara Y. Genomic analysis of Borrelia japonica sp. nov. isolated from Ixodes ovatus in Japan. Microbiol Immunol. 1993;37(11):843–848. doi: 10.1111/j.1348-0421.1993.tb01714.x. [DOI] [PubMed] [Google Scholar]
  31. Livey I., Gibbs C. P., Schuster R., Dorner F. Evidence for lateral transfer and recombination in OspC variation in Lyme disease Borrelia. Mol Microbiol. 1995 Oct;18(2):257–269. doi: 10.1111/j.1365-2958.1995.mmi_18020257.x. [DOI] [PubMed] [Google Scholar]
  32. Luft B. J., Mudri S., Jiang W., Dattwyler R. J., Gorevic P. D., Fischer T., Munoz P., Dunn J. J., Schubach W. H. The 93-kilodalton protein of Borrelia burgdorferi: an immunodominant protoplasmic cylinder antigen. Infect Immun. 1992 Oct;60(10):4309–4321. doi: 10.1128/iai.60.10.4309-4321.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Magnarelli L. A., Anderson J. F., Fish D. Transovarial transmission of Borrelia burgdorferi in Ixodes dammini (Acari:Ixodidae). J Infect Dis. 1987 Jul;156(1):234–236. doi: 10.1093/infdis/156.1.234. [DOI] [PubMed] [Google Scholar]
  34. Magnarelli L. A., Flavell R. A., Padula S. J., Anderson J. F., Fikrig E. Serologic diagnosis of canine and equine borreliosis: use of recombinant antigens in enzyme-linked immunosorbent assays. J Clin Microbiol. 1997 Jan;35(1):169–173. doi: 10.1128/jcm.35.1.169-173.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Masuzawa T., Komikado T., Yanagihara Y. PCR-restriction fragment length polymorphism analysis of the ospC gene for detection of mixed culture and for epidemiological typing of Borrelia burgdorferi sensu stricto. Clin Diagn Lab Immunol. 1997 Jan;4(1):60–63. doi: 10.1128/cdli.4.1.60-63.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Mathiesen M. J., Hansen K., Axelsen N., Halkier-Sørensen L., Theisen M. Analysis of the human antibody response to outer surface protein C (OspC) of Borrelia burgdorferi sensu stricto, B. garinii, and B. afzelii. Med Microbiol Immunol. 1996 Nov;185(3):121–129. doi: 10.1007/s004300050021. [DOI] [PubMed] [Google Scholar]
  37. Nei M., Gojobori T. Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol. 1986 Sep;3(5):418–426. doi: 10.1093/oxfordjournals.molbev.a040410. [DOI] [PubMed] [Google Scholar]
  38. Nei M., Jin L. Variances of the average numbers of nucleotide substitutions within and between populations. Mol Biol Evol. 1989 May;6(3):290–300. doi: 10.1093/oxfordjournals.molbev.a040547. [DOI] [PubMed] [Google Scholar]
  39. Padula S. J., Dias F., Sampieri A., Craven R. B., Ryan R. W. Use of recombinant OspC from Borrelia burgdorferi for serodiagnosis of early Lyme disease. J Clin Microbiol. 1994 Jul;32(7):1733–1738. doi: 10.1128/jcm.32.7.1733-1738.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Padula S. J., Sampieri A., Dias F., Szczepanski A., Ryan R. W. Molecular characterization and expression of p23 (OspC) from a North American strain of Borrelia burgdorferi. Infect Immun. 1993 Dec;61(12):5097–5105. doi: 10.1128/iai.61.12.5097-5105.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Persing D. H., Mathiesen D., Podzorski D., Barthold S. W. Genetic stability of Borrelia burgdorferi recovered from chronically infected immunocompetent mice. Infect Immun. 1994 Aug;62(8):3521–3527. doi: 10.1128/iai.62.8.3521-3527.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Picken R. N., Cheng Y., Han D., Nelson J. A., Reddy A. G., Hayden M. K., Picken M. M., Strle F., Bouseman J. K., Trenholme G. M. Genotypic and phenotypic characterization of Borrelia burgdorferi isolated from ticks and small animals in Illinois. J Clin Microbiol. 1995 Sep;33(9):2304–2315. doi: 10.1128/jcm.33.9.2304-2315.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Postic D., Assous M. V., Grimont P. A., Baranton G. Diversity of Borrelia burgdorferi sensu lato evidenced by restriction fragment length polymorphism of rrf (5S)-rrl (23S) intergenic spacer amplicons. Int J Syst Bacteriol. 1994 Oct;44(4):743–752. doi: 10.1099/00207713-44-4-743. [DOI] [PubMed] [Google Scholar]
  44. Preac-Mursic V., Wilske B., Patsouris E., Jauris S., Will G., Soutschek E., Rainhardt S., Lehnert G., Klockmann U., Mehraein P. Active immunization with pC protein of Borrelia burgdorferi protects gerbils against B. burgdorferi infection. Infection. 1992 Nov-Dec;20(6):342–349. doi: 10.1007/BF01710681. [DOI] [PubMed] [Google Scholar]
  45. Probert W. S., Crawford M., Cadiz R. B., LeFebvre R. B. Immunization with outer surface protein (Osp) A, but not OspC, provides cross-protection of mice challenged with North American isolates of Borrelia burgdorferi. J Infect Dis. 1997 Feb;175(2):400–405. doi: 10.1093/infdis/175.2.400. [DOI] [PubMed] [Google Scholar]
  46. Probert W. S., LeFebvre R. B. Protection of C3H/HeN mice from challenge with Borrelia burgdorferi through active immunization with OspA, OspB, or OspC, but not with OspD or the 83-kilodalton antigen. Infect Immun. 1994 May;62(5):1920–1926. doi: 10.1128/iai.62.5.1920-1926.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Qiu W. G., Bosler E. M., Campbell J. R., Ugine G. D., Wang I. N., Luft B. J., Dykhuizen D. E. A population genetic study of Borrelia burgdorferi sensu stricto from eastern Long Island, New York, suggested frequency-dependent selection, gene flow and host adaptation. Hereditas. 1997;127(3):203–216. doi: 10.1111/j.1601-5223.1997.00203.x. [DOI] [PubMed] [Google Scholar]
  48. Riley M. A. Positive selection for colicin diversity in bacteria. Mol Biol Evol. 1993 Sep;10(5):1048–1059. doi: 10.1093/oxfordjournals.molbev.a040054. [DOI] [PubMed] [Google Scholar]
  49. Rosa P. A., Schwan T., Hogan D. Recombination between genes encoding major outer surface proteins A and B of Borrelia burgdorferi. Mol Microbiol. 1992 Oct;6(20):3031–3040. doi: 10.1111/j.1365-2958.1992.tb01761.x. [DOI] [PubMed] [Google Scholar]
  50. Sandberg S., Awerbuch T. E., Spielman A. A comprehensive multiple matrix model representing the life cycle of the tick that transmits the agent of Lyme disease. J Theor Biol. 1992 Jul 21;157(2):203–220. doi: 10.1016/s0022-5193(05)80621-6. [DOI] [PubMed] [Google Scholar]
  51. 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]
  52. Seibert S. A., Howell C. Y., Hughes M. K., Hughes A. L. Natural selection on the gag, pol, and env genes of human immunodeficiency virus 1 (HIV-1). Mol Biol Evol. 1995 Sep;12(5):803–813. doi: 10.1093/oxfordjournals.molbev.a040257. [DOI] [PubMed] [Google Scholar]
  53. Simon M. M., Schaible U. E., Kramer M. D., Eckerskorn C., Museteanu C., Müller-Hermelink H. K., Wallich R. Recombinant outer surface protein a from Borrelia burgdorferi induces antibodies protective against spirochetal infection in mice. J Infect Dis. 1991 Jul;164(1):123–132. doi: 10.1093/infdis/164.1.123. [DOI] [PubMed] [Google Scholar]
  54. Slatkin M. A correction to the exact test based on the Ewens sampling distribution. Genet Res. 1996 Dec;68(3):259–260. doi: 10.1017/s0016672300034236. [DOI] [PubMed] [Google Scholar]
  55. Slatkin M. An exact test for neutrality based on the Ewens sampling distribution. Genet Res. 1994 Aug;64(1):71–74. doi: 10.1017/s0016672300032560. [DOI] [PubMed] [Google Scholar]
  56. Spielman A. Prospects for suppressing transmission of Lyme disease. Ann N Y Acad Sci. 1988;539:212–220. doi: 10.1111/j.1749-6632.1988.tb31855.x. [DOI] [PubMed] [Google Scholar]
  57. Stevenson B., Bockenstedt L. K., Barthold S. W. Expression and gene sequence of outer surface protein C of Borrelia burgdorferi reisolated from chronically infected mice. Infect Immun. 1994 Aug;62(8):3568–3571. doi: 10.1128/iai.62.8.3568-3571.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Stevenson B., Schwan T. G., Rosa P. A. Temperature-related differential expression of antigens in the Lyme disease spirochete, Borrelia burgdorferi. Infect Immun. 1995 Nov;63(11):4535–4539. doi: 10.1128/iai.63.11.4535-4539.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Tajima F. Determination of window size for analyzing DNA sequences. J Mol Evol. 1991 Nov;33(5):470–473. doi: 10.1007/BF02103140. [DOI] [PubMed] [Google Scholar]
  60. Theisen M., Borre M., Mathiesen M. J., Mikkelsen B., Lebech A. M., Hansen K. Evolution of the Borrelia burgdorferi outer surface protein OspC. J Bacteriol. 1995 Jun;177(11):3036–3044. doi: 10.1128/jb.177.11.3036-3044.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Theisen M., Frederiksen B., Lebech A. M., Vuust J., Hansen K. Polymorphism in ospC gene of Borrelia burgdorferi and immunoreactivity of OspC protein: implications for taxonomy and for use of OspC protein as a diagnostic antigen. J Clin Microbiol. 1993 Oct;31(10):2570–2576. doi: 10.1128/jcm.31.10.2570-2576.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Valsangiacomo C., Balmelli T., Piffaretti J. C. A phylogenetic analysis of Borrelia burgdorferi sensu lato based on sequence information from the hbb gene, coding for a histone-like protein. Int J Syst Bacteriol. 1997 Jan;47(1):1–10. doi: 10.1099/00207713-47-1-1. [DOI] [PubMed] [Google Scholar]
  63. Vidal-Puig A., Moller D. E. Comparative sensitivity of alternative single-strand conformation polymorphism (SSCP) methods. Biotechniques. 1994 Sep;17(3):490-2, 494, 496. [PubMed] [Google Scholar]
  64. Wagner R. R., Riley M. A. Low synonymous site variation at the lacY locus in Escherichia coli suggests the action of positive selection. J Mol Evol. 1996 Feb;42(2):79–84. doi: 10.1007/BF02198831. [DOI] [PubMed] [Google Scholar]
  65. Wilske B., Preac-Mursic V., Jauris S., Hofmann A., Pradel I., Soutschek E., Schwab E., Will G., Wanner G. Immunological and molecular polymorphisms of OspC, an immunodominant major outer surface protein of Borrelia burgdorferi. Infect Immun. 1993 May;61(5):2182–2191. doi: 10.1128/iai.61.5.2182-2191.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Wilson M. L., Spielman A. Seasonal activity of immature Ixodes dammini (Acari: Ixodidae). J Med Entomol. 1985 Jul 26;22(4):408–414. doi: 10.1093/jmedent/22.4.408. [DOI] [PubMed] [Google Scholar]
  67. Yuval B., Spielman A. Duration and regulation of the developmental cycle of Ixodes dammini (Acari: Ixodidae). J Med Entomol. 1990 Mar;27(2):196–201. doi: 10.1093/jmedent/27.2.196. [DOI] [PubMed] [Google Scholar]
  68. Zhong W., Stehle T., Museteanu C., Siebers A., Gern L., Kramer M., Wallich R., Simon M. M. Therapeutic passive vaccination against chronic Lyme disease in mice. Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12533–12538. doi: 10.1073/pnas.94.23.12533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. van Dam A. P., Kuiper H., Vos K., Widjojokusumo A., de Jongh B. M., Spanjaard L., Ramselaar A. C., Kramer M. D., Dankert J. Different genospecies of Borrelia burgdorferi are associated with distinct clinical manifestations of Lyme borreliosis. Clin Infect Dis. 1993 Oct;17(4):708–717. doi: 10.1093/clinids/17.4.708. [DOI] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES