Lyme Disease: A Neuropsychiatric Illness

(in cache)

Brian A. Fallon, M.D., M.P.H., Jenifer A. Nields, M.D.

Special Article, The American Journal of Psychiatry 1994, 151:11, 1571-1583.

Microbiology of Borrelia burgdorferi

The microbiology of B. burgdorferi sheds light on why Lyme disease is an illness that at times can be relapsing and remitting and that can be refractory to normal immune surveillance and standard antibiotic regimens.

The causative agent of Lyme disease -the spirochete B. burgdorferi- has a long replication time, comparable in this respect to Mycobacterium tuberculosis.
Rapidly transmitted throughout the body, B. burgdorferi is known to invade the central nervous system (CNS) within the first few weeks after infection (20 - 22).
B. burgdorferi is known to be neurotropic, leaving the cerebrospinal fluid (CSF) to adhere to glial cells or other brain tissue (75).
Once in the CNS, B. burgdorferi, like Treponema pallidum, may remain latent, only to cause illness months later (23).

Much of the genetic material in B. burgdorferi is contained in plasmids (76), resulting in the possibility of significant variability. This includes

marked variability in the expression of surface antigens, with consequent alterations in immunogenicity. Such changes could lead to

resistance to normal immunologic functions -for example, through a failure of the B. burgdorferi-specific antibody to induce phagocytosis- as well as to
evasion of routine laboratory detection.

Recent animal research (77) has found that the spirochete may undergo genetic alteration once it is sequestered in the CNS, thus resulting in a new strain of spirochete that is different from the infecting peripheral spirochete. The remarkable strain variation of B. burgdorferi may account for the differences between the presentation of Lyme disease in Europe and in the United States (78, 80). For example,

in Continental Europe, arthritic involvement is less common, and most cases of neurologic Lyme disease have prominent CSF abnormalities.
Late-stage neurologic Lyme disease in the United States, on the other hand, is less likely to show CSF abnormalities on routine testing (81).

During growth, Bb appears to shed membranous material (blebs) from its surface. These blebs coat the spirochete and have been found free in the CSF, serum, and urine (21, 82, 83).

The blebs appear to interact specifically with IgM molecules. It is hypothesized that in some cases, the blebs may bind all of the free circulating B. burgdorferi-specific IgM antibodies (Schutzer et al. 1994), thereby enabling the organism itself to escape immune surveillance (Lawrence et al. 1995).
In addition, the blebs possess potent, nonspecific mitogenic activity that may cause an inappropriate and ineffective stimultation of the immune system (Ma et al. 1993). This could initiate autoimmune disease processes (84).

B. burgdorferi has been shown to be capable of persisting in human hosts despite extensive antibiotic treatment (17, 85 - 88). Because in vitro studies demonstrate that B. burgdorferi

can be recovered from antibiotic-treated fibroblast monolayers (89) and because B. burgdorferi has been shown to
lodge inside

human fibroblasts (89),
mouse macrophages (90), and
human endothelial cells (91),

researchers conclude that the intracellular location may enable the spirochete to remain inaccessible to (such) antibiotics (that do not enter into cells, see Brouqui et al. 1996, parenthesis by J. Gruber) and normal immune surveillance. Sequestration in other antibiotic- and immunologically priviledged sites

(e.g.

CNS,
joints,
anterior chamber of the eye)

may also account for persistent illness despite antibiotic treatment (20).

Several features are known to contribute to an organism's resistance to standard lengths of antibiotic treatment. These features include

an intracellular location (92),
long replication time,
genetic variablity, and
the ability to become sequestered in difficult-to-penetrate sites.

B. burgdorferi appears to possess all of these characteristics.

References

17. Liegner KB: Lyme disease: the sensible pursuit of answers. J Clin Microbiol 1993; 31: 1961-1963.

20. Luft BJ, Steinman CR, Neimark HC, Muralidhar B, Rush T, Finkel MF, Kunkel M, Dattwyler RJ: Invasion of the CNS by Bb in acute disseminated infection. JAMA 1992; 267:1364-1367.

21. Coyle PK, Deng Z, Schutzer SF, Belman AL, Benach J, Krupp LB, Luft B: Detection of Bb antigens in cerebrospinal fluid. Neurology 1993, 43: 1093-1097.

22. Garcia-Monco JC, Villar BF, Alen JC, Benach JL: Borrelia burgdorferi in the central nervous system: experimental and clinical evidence for early invasion. J Infect Dis 1990; 161:1187-1193.

23. Loggian EL, Kaplan RF, Steere AC: Chronic neurologic manifestation of Lyme disease. N Engl J Med 1990; 323:1483-1444.

75. Garcia-Monco JC, Fernandez-Villar B, Benach JL: Adherence of the Lyme disease spirochete to glial cells and cells of glial origin. J Infect Dis 1989; 160: 497-506.

76. Barbour AG, Garon CF: Linear plasmids of the bacterium Borrelia burgdorferi have covalently closed ends. Science 1987; 237: 409-411.

77. Pachner AR, 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; 40: 1535-1540.

78. Hanrahan JP, Benach JL, Coleman JL, Bosler EM, Morse DL, Cameron DJ, Edelman R, Kaslow RA: J Infect Dis 1984; 150: 489-596.

79. Steere AC, Taylor E, Wilson ML, Levine JL, Spielman A: Longitudinal assessmentr of the clinical and epidemiological features of Lyme disease in a defined population. J Infect Dis 1986; 154: 295-300.

80. Schwan TG, Burgdorfer W, Garon CF: Changes in infectivity and plasmid profile of the Lyme disease spirochete, Borrelia burgdorferi, as a result of in vitro cultivation. Infect Immun 1988; 56: 1831-1836.

81. Coyle PK: Antigen detection and cerebrospinal fluid studies, in: "Lyme Disease", Coyle PK (ed.), Philadelphia, Mosby Year Book, 1992.

82. Garon CF, Dorward DW, Corwin MD: Structural features of Bb - the Lyme disease spirochete silver staining for nucleic acids, Scanning Microsc. Suppl 1989, 3: 109-115.

83. Dorward DW, Schwan TG, Garon CF: Immune capture and detection of Bb antigens in urine, blood, or tissues from infected ticks, mice, dogs, and humans, J Clin Microbiol 1991; 29: 1162-1170.

84. Whitmire WM, Garon CF: Specific and nonspecific responses of murine B cells to membrane blebs of Borrelia burgdorferi. Infect Immun 1993; 61: 1460-1467.

85. Preac-Mursic V, Weber K, Pfister HW, Wilske B, Gross B, Baumann A, Prokop J: Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis. Infection 1989; 17: 355-359.

86. Haupl T, Hahn G, Rittig M, Krause A, Schoerner C, Schonherr U, Kalden JR, Burmester GR: Persistence of Borrelia burgdorferi in ligamentous tissue from a patient with chronic Lyme borreliosis. Arthritis Rheum 1993;, 36: 1621-1626.

87. Hassler D, Riedel K, Zorn J, Preac-Mursic V: Pulsed high-dose cefotaxime therapy in refractory Lyme borreliosis (letter). Lancet 1991; 338: 193.

88. Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L: Recurrence erythema migrans despite extended antibiotic treatment with monocycline in a patient with persisting Borrelia burgdorferi infection. J Am Acad Dermatol 1993; 28: 312-314.

89. Georgilis K, Peacocke M, Klempner MS: Fibroblasts protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro. J Infect Dis 1992: 166: 440-444.

90. Montgomery RR, Nathanson MH, Malawista SE: The fate of Borrelia burgdorferi in mouse macrophages: destruction, survival, recovery. J Immunol 1993; 150: 909-915.

91. Ma Y, Sturrock A, Weis JJ: Intracellular localization of Borrelia burgdorferi within human endothelial cells. Infect Immun 1991; 59: 671-678.

92. Mahmoud AA: The challenge of intracellular pathogens (editorial) N Engl J Med 1992; 326: 761-762.

The following references, cited by name rather than by numbers, have been added by Dr. J. Gruber.

P. Brouqui, S. Badiaga, D. Raoult: Eucaryotic Cells Protect Borrelia burgdorferi from the Action of Penicillin and Ceftriaxone but Not from the Action of Doxycycline and Erythromycin: NOTES.Antimicrobial Agents and Chemotherapy 1996:1552Ð1554.

Lawrence C, Lipton RB, Lowy FD, Coyle PK: Seronegative chronic relapsing neuroborreliosis. Eur Neurol 1995;35(2):113-117.

Ma Y, Weis JJ: Borrelia burgdorferi outer surface lipoproteins OspA and OspB possess B-cell mitogenic and cytokine-stimulatory properties. Infect Immun 1993 Sep;61(9):3843-53.

Schutzer SE, Coyle PK, Dunn JJ, Luft BJ, Brunner M: Early and specific antibody response to OspA in Lyme Disease. J Clin Invest 1994 Jul;94(1):454-457.

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Version: October 21, 2008.

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