Abstract
During persistent infection of scid mice with Borrelia turicatae, an agent of relapsing fever and neuroborreliosis, there was variation in the surface proteins the bacteria expressed and in disease manifestations over time. Two serotypes, A and B, were isolated from the mice, cloned by limiting dilution, and further characterized. The only discernible difference between the two variants was in the size of the major surface protein they expressed: serotype A had a variable major protein (Vmp) of 23,000, and serotype B had a Vmp of 20,000. When other scid mice were inoculated with clonal populations of A and B, the infections were similar with respect to onset and degree of spirochetemia, involvement of the eye and heart, and occurrence of a peripheral vestibular disorder. However, there were differences between the serotypes in other respects: (a) serotype B but not A caused reddened and significantly enlarged joints, markedly impaired performance on a walking bar, and severe arthritis by histologic examination; (b) serotype A but not B invaded the central nervous system during early infection; and (c) serotype A penetrated monolayers of human umbilical vein endothelial cells more readily than did serotype B. The combination of arthritis, myocarditis, and neurologic disease resembled human Lyme borreliosis. The findings indicate that differences in disease expression are determined by variable surface proteins of the bacterium and that scid mouse infections with B. turicatae provide a model for the study of the pathogenesis of Lyme borreliosis and other persistent spirochetal diseases.
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- Anderson J. F., Barthold S. W., Magnarelli L. A. Infectious but nonpathogenic isolate of Borrelia burgdorferi. J Clin Microbiol. 1990 Dec;28(12):2693–2699. doi: 10.1128/jcm.28.12.2693-2699.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Barbour A. G. Antigenic variation of a relapsing fever Borrelia species. Annu Rev Microbiol. 1990;44:155–171. doi: 10.1146/annurev.mi.44.100190.001103. [DOI] [PubMed] [Google Scholar]
- 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]
- Barbour A. G., Hayes S. F. Biology of Borrelia species. Microbiol Rev. 1986 Dec;50(4):381–400. doi: 10.1128/mr.50.4.381-400.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Barbour A. G., Tessier S. L., Stoenner H. G. Variable major proteins of Borrellia hermsii. J Exp Med. 1982 Nov 1;156(5):1312–1324. doi: 10.1084/jem.156.5.1312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Barstad P. A., Coligan J. E., Raum M. G., Barbour A. G. Variable major proteins of Borrelia hermsii. Epitope mapping and partial sequence analysis of CNBr peptides. J Exp Med. 1985 Jun 1;161(6):1302–1314. doi: 10.1084/jem.161.6.1302. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Barthold S. W., Moody K. D., Terwilliger G. A., Duray P. H., Jacoby R. O., Steere A. C. Experimental Lyme arthritis in rats infected with Borrelia burgdorferi. J Infect Dis. 1988 Apr;157(4):842–846. doi: 10.1093/infdis/157.4.842. [DOI] [PubMed] [Google Scholar]
- Blaauw A. A., Nohlmans M. K., Leffers P., Goei The H. S., van der Linden S. Lyme borreliosis: a very infrequent cause of arthritis of undetermined aetiology in the southern part of The Netherlands. Br J Rheumatol. 1992 Jun;31(6):401–404. doi: 10.1093/rheumatology/31.6.401. [DOI] [PubMed] [Google Scholar]
- Cadavid D., Bundoc V., Barbour A. G. Experimental infection of the mouse brain by a relapsing fever Borrelia species: a molecular analysis. J Infect Dis. 1993 Jul;168(1):143–151. doi: 10.1093/infdis/168.1.143. [DOI] [PubMed] [Google Scholar]
- Comstock L. E., Thomas D. D. Penetration of endothelial cell monolayers by Borrelia burgdorferi. Infect Immun. 1989 May;57(5):1626–1628. doi: 10.1128/iai.57.5.1626-1628.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dean R. L., 3rd, Scozzafava J., Goas J. A., Regan B., Beer B., Bartus R. T. Age-related differences in behavior across the life span of the C57BL/6J mouse. Exp Aging Res. 1981 Winter;7(4):427–451. doi: 10.1080/03610738108259823. [DOI] [PubMed] [Google Scholar]
- Greenberg E. P., Canale-Parola E. Chemotaxis in Spirochaeta aurantia. J Bacteriol. 1977 Apr;130(1):485–494. doi: 10.1128/jb.130.1.485-494.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Johnson R. C., Marek N., Kodner C. Infection of Syrian hamsters with Lyme disease spirochetes. J Clin Microbiol. 1984 Dec;20(6):1099–1101. doi: 10.1128/jcm.20.6.1099-1101.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kitten T., Barbour A. G. Juxtaposition of expressed variable antigen genes with a conserved telomere in the bacterium Borrelia hermsii. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6077–6081. doi: 10.1073/pnas.87.16.6077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kornblatt A. N., Steere A. C., Brownstein D. G. Experimental Lyme disease in rabbits: spirochetes found in erythema migrans and blood. Infect Immun. 1984 Oct;46(1):220–223. doi: 10.1128/iai.46.1.220-223.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Luft B. J., Jiang W., Munoz P., Dattwyler R. J., Gorevic P. D. Biochemical and immunological characterization of the surface proteins of Borrelia burgdorferi. Infect Immun. 1989 Nov;57(11):3637–3645. doi: 10.1128/iai.57.11.3637-3645.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meier J. T., Simon M. I., Barbour A. G. Antigenic variation is associated with DNA rearrangements in a relapsing fever Borrelia. Cell. 1985 Jun;41(2):403–409. doi: 10.1016/s0092-8674(85)80013-1. [DOI] [PubMed] [Google Scholar]
- Newman K., Jr, Johnson R. C. T-cell-independent elimination of Borrelia turicatae. Infect Immun. 1984 Sep;45(3):572–576. doi: 10.1128/iai.45.3.572-576.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nonoyama S., Smith F. O., Bernstein I. D., Ochs H. D. Strain-dependent leakiness of mice with severe combined immune deficiency. J Immunol. 1993 May 1;150(9):3817–3824. [PubMed] [Google Scholar]
- Pachner A. R., Itano A. Borrelia burgdorferi infection of the brain: characterization of the organism and response to antibiotics and immune sera in the mouse model. Neurology. 1990 Oct;40(10):1535–1540. doi: 10.1212/wnl.40.10.1535. [DOI] [PubMed] [Google Scholar]
- Preac Mursic V., Patsouris E., Wilske B., Reinhardt S., Gross B., Mehraein P. Persistence of Borrelia burgdorferi and histopathological alterations in experimentally infected animals. A comparison with histopathological findings in human Lyme disease. Infection. 1990 Nov-Dec;18(6):332–341. doi: 10.1007/BF01646399. [DOI] [PubMed] [Google Scholar]
- Randall L. L., Hardy S. J. Correlation of competence for export with lack of tertiary structure of the mature species: a study in vivo of maltose-binding protein in E. coli. Cell. 1986 Sep 12;46(6):921–928. doi: 10.1016/0092-8674(86)90074-7. [DOI] [PubMed] [Google Scholar]
- Restrepo B. I., Kitten T., Carter C. J., Infante D., Barbour A. G. Subtelomeric expression regions of Borrelia hermsii linear plasmids are highly polymorphic. Mol Microbiol. 1992 Nov;6(22):3299–3311. doi: 10.1111/j.1365-2958.1992.tb02198.x. [DOI] [PubMed] [Google Scholar]
- SCHUHARDT V. T., WILKERSON M. Relapse phenomena in rats infected with single spirochetes (Borrelia recurrentis var. turicatae). J Bacteriol. 1951 Aug;62(2):215–219. doi: 10.1128/jb.62.2.215-219.1951. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sadziene A., Barbour A. G., Rosa P. A., Thomas D. D. An OspB mutant of Borrelia burgdorferi has reduced invasiveness in vitro and reduced infectivity in vivo. Infect Immun. 1993 Sep;61(9):3590–3596. doi: 10.1128/iai.61.9.3590-3596.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sakić B., Szechtman H., Keffer M., Talangbayan H., Stead R., Denburg J. A. A behavioral profile of autoimmune lupus-prone MRL mice. Brain Behav Immun. 1992 Sep;6(3):265–285. doi: 10.1016/0889-1591(92)90048-s. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Schaible U. E., Kramer M. D., Wallich R., Tran T., Simon M. M. Experimental Borrelia burgdorferi infection in inbred mouse strains: antibody response and association of H-2 genes with resistance and susceptibility to development of arthritis. Eur J Immunol. 1991 Oct;21(10):2397–2405. doi: 10.1002/eji.1830211016. [DOI] [PubMed] [Google Scholar]
- Steere A. C., Dwyer E., Winchester R. Association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles. N Engl J Med. 1990 Jul 26;323(4):219–223. doi: 10.1056/NEJM199007263230402. [DOI] [PubMed] [Google Scholar]
- Steere A. C. Lyme disease. N Engl J Med. 1989 Aug 31;321(9):586–596. doi: 10.1056/NEJM198908313210906. [DOI] [PubMed] [Google Scholar]
- Steere A. C., Schoen R. T., Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med. 1987 Nov;107(5):725–731. doi: 10.7326/0003-4819-107-5-725. [DOI] [PubMed] [Google Scholar]
- Stoenner H. G., Dodd T., Larsen C. Antigenic variation of Borrelia hermsii. J Exp Med. 1982 Nov 1;156(5):1297–1311. doi: 10.1084/jem.156.5.1297. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stover C. K., Bansal G. P., Hanson M. S., Burlein J. E., Palaszynski S. R., Young J. F., Koenig S., Young D. B., Sadziene A., Barbour A. G. Protective immunity elicited by recombinant bacille Calmette-Guerin (BCG) expressing outer surface protein A (OspA) lipoprotein: a candidate Lyme disease vaccine. J Exp Med. 1993 Jul 1;178(1):197–209. doi: 10.1084/jem.178.1.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sădziene A., Rosa P. A., Thompson P. A., Hogan D. M., Barbour A. G. Antibody-resistant mutants of Borrelia burgdorferi: in vitro selection and characterization. J Exp Med. 1992 Sep 1;176(3):799–809. doi: 10.1084/jem.176.3.799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weiner H. L., Drayna D., Averill D. R., Jr, Fields B. N. Molecular basis of reovirus virulence: role of the S1 gene. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5744–5748. doi: 10.1073/pnas.74.12.5744. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilske B., Barbour A. G., Bergström S., Burman N., Restrepo B. I., Rosa P. A., Schwan T., Soutschek E., Wallich R. Antigenic variation and strain heterogeneity in Borrelia spp. Res Microbiol. 1992 Jul-Aug;143(6):583–596. doi: 10.1016/0923-2508(92)90116-6. [DOI] [PubMed] [Google Scholar]