Lyme disease microbiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

Borrelia burgdorferi the causative agent of Lyme disease (borreliosis). Magnified 400 times.

Lyme disease, or Lyme borreliosis, is caused by Gram negative spirochetal bacteria from the genus Borrelia, which has at least 37 known species, 12 of which are Lyme related, and an unknown number of genomic strains. Borrelia species known to cause Lyme disease are collectively known as Borrelia burgdorferi sensu lato.

Borrelia are microaerophillic and slow-growing—the primary reason for the long delays when diagnosing Lyme disease—and have been found to have greater strain diversity than previously estimated.[1] The strains differ in clinical symptoms and/or presentation as well as geographic distribution.[2]

Except for Borrelia recurrentis (which causes louse-borne relapsing fever and is transmitted by the human body louse), all known species are believed to be transmitted by ticks.[3]

Species and Strains

Until recently it was thought that only three genospecies caused Lyme disease (borreliosis): B. burgdorferi sensu stricto ( the predominant species in North America, but also present in Europe); B. afzelii; and B. garinii (both predominant in Eurasia). To date the complete genome of B. burgdorferi sensu stricto strain B31, B. afzelii strain PKo and B. garinii strain PBi is known. B. burgdorferi strain B31 was derived by limited dilutional cloning from the original Lyme-disease tick isolate derived by Alan Barbour. There are over 300 species or strains of Borrelia world wide with apx 100 in the U.S. and it is unknown how many cause lyme like sickness, but many of them may.

At present, diagnostic tests are based only on B. burgdorferi sensu stricto (the only species used in the U.S.), B. afzelii, and B. garinii.

Emerging Genospecies

  • B. valaisiana was identified as a genomic species from Strain VS116, and named B. valaisiana in 1997.[4] It was later detected by Polymerase chain reaction (PCR) in human cerebral spinal fluid (CSF) in Greece.[5] B. valaisiana has been isolated throughout Europe, as well east Asia.[6]

Newly discovered genospecies have also been found to cause disease in humans:

  • B. lusitaniae [7] in Europe (especially Portugal), North Africa and Asia.
  • B. bissettii [8][9] in the U.S. and Europe.

Additional B. burgdorferi sensu lato genospecies suspected of causing illness, but not confirmed by culture, include B. japonica, B. tanukii and B. turdae (Japan); B. sinica (China); and B. andersonii (U.S.). Some of these species are carried by ticks not currently recognized as carriers of Lyme disease.

The B. miyamotoi spirochete, related to the relapsing fever group of spirochetes, is also suspected of causing illness in Japan. Spirochetes similar to B. miyamotoi have recently been found in both I. ricinus ticks in Sweden and I. scapularis ticks in the U.S.[12][13]

B. lonestari

Apart from this group of closely related genospecies, additional Borrelia species of interest include B. lonestari, a spirochete recently detected in the Amblyomma americanum tick (Lone Star tick) in the U.S.[14] B. lonestari is suspected of causing STARI (Southern Tick-Associated Rash Illness), also known as Masters disease in honor of its discoverer Ed Masters. The illness follows a Lone Star tick bite and clinically resembles Lyme disease, but sufferers usually test negative for Lyme.[15]There is currently no diagnostic test available for STARI/Masters, and no official treatment protocol, though antibiotics are generally prescribed.


Genomic characteristics

One of the most striking features of B. burgdorferi as compared with other eubacteria is its unusual genome, which is far more complex than that of its spirochetal cousin Treponema pallidum, the agent of syphilis.[16] The genome of B. burgdorferi includes a linear chromosome approximately one megabase in size, with 21 plasmids (12 linear and 9 circular) - by far the largest number of plasmids found in any known bacterium.[17] Genetic exchange, including plasmid transfers, contributes to the pathogenicity of the organism.[18] Long-term culture of B. burgdorferi results in a loss of some plasmids and changes in expressed protein profiles. Associated with the loss of plasmids is a loss in the ability of the organism to infect laboratory animals, suggesting that the plasmids encode key genes involved in virulence.

Chemical analysis of the external membrane of B. burgdorferi revealed the presence of 46% proteins, 51% lipids and 3% carbohydrates.[19]


Mechanisms of persistence

While B. burgdorferi is susceptible to a number of antibiotics in vitro, there are contradictory reports as to the efficacy of antibiotics in vivo. B. burgdorferi may persist in humans and animals for months or years despite a robust immune response and standard antibiotic treatment, particularly when treatment is delayed and dissemination widespread. Numerous studies have demonstrated persistence of infection despite antibiotic therapy.[20][21][22]

Various survival strategies of B. burgdorferi have been posited to explain this phenomenon,[23] including the following:

B. burgdorferi has been shown to invade a variety of cells, including endothelium,[26] fibroblasts,[27] lymphocytes,[28] macrophages,[29] keratinocytes,[30] synovium,[31][32] and most recently neuronal and glial cells. [33] By 'hiding' inside these cells, B. burgdorferi is able to evade the immune system and is protected to varying degrees against antibiotics,[34][35] allowing the infection to persist in a chronic state.

The existence of B. burgdorferi spheroplasts, which lack a cell wall, has been documented in vitro,[36][37][38][39] in vivo,[32][37][40] and in an ex vivo model.[41] The fact that energy is required for the spiral bacterium to convert to the cystic form[36] suggests that these altered forms have a survival function, and are not merely end stage degeneration products. The spheroplasts are indeed virulent and infectious, able to survive under adverse environmental conditions, and have been shown to revert back to the spiral form in vitro, once conditions are more favorable.[42][43]

A number of other factors make B. burgdorferi spheroplasts a key factor in the relapsing, chronic nature of Lyme disease. Compared to the spiral form, spheroplasts have dramatically reduced surface area for immune surveillance. They also express different surface proteins - another reason for seronegative disease (i.e. false-negative antibody tests), as current tests only look for antibodies to surface proteins of the spiral form. In addition, B. burgdorferi spheroplasts are generally not susceptible to the antibiotics traditionally used for Lyme disease. They have instead shown sensitivity in vitro to antiparasitic drugs such as metronidazole, [44] tinidazole, [45] and hydroxychloroquine, [46] to which the spiral form of B. burgdorferi is not sensitive.

Like the Borrelia that cause relapsing fever, B. burgdorferi has the ability to vary its surface proteins in response to immune attack.[23][47] This ability is related to the genomic complexity of B. burgdorferi, and is another way B. burgdorferi evades the immune system to establish a chronic infection.[48]

Complement inhibition, induction of anti-inflammatory cytokines such as IL-10, and the formation of immune complexes have all been documented in B. burgdorferi infection.[23] Furthermore, the existence of immune complexes provides another explanation for seronegative disease (i.e. false-negative antibody tests of blood and cerebrospinal fluid), as studies have shown that substantial numbers of seronegative Lyme patients have antibodies bound up in these complexes.[49]

Advancing Immunology Research

Further information: Lyme Disease § Advancing Immunology Research

The role of T cells in borrelia was first made in 1984,[50] the role of cellular immunity in active Lyme disease was made in 1986,[51] and long term persistence of T cell lymphocyte responses to B. burgdorferi as an "immunological scar syndrome" was hypothesized in 1990.[52] The role Th1 and interferon-gamma (INF-gamma) in borrelia was first described in 1995.[53] The cytokine pattern of Lyme disease, and the role of Th1 with down regulation of interleukin-10 (IL-10) was first proposed in 1997.[54]

Recent studies in both acute and antibiotic refractory, or chronic, Lyme disease have shown a distinct pro-inflammatory immune process. This pro-inflammatory process is a cell-mediated immunity and results in Th1 upregulation. These studies have shown a significant decrease in cytokine output of (IL-10), an upregulation of Interleukin-6 (IL-6) and Interleukin-12 (Il-12) and Interferon-gamma (IFN-gamma) and disregulation in TNF-alpha predominantly.

New research has also found that chronic Lyme patients have higher amounts of Borrelia-specific forkhead box P3 (FoxP3) than healthy controls, indicating that regulatory T cells might also play a role, by immunosuppression, in the development of chronic Lyme disease. FoxP3 are a specific marker of regulatory T cells.[55] The signaling pathway P38 mitogen-activated protein kinases (p38 MAP kinase) has also been identified as promoting expression of proinflammatory cytokines from borrelia.[56][57]

The culmination of these new and ongoing immunological studies suggest this cell-mediated immune disruption in the Lyme patient amplifies the inflammatory process, often rendering it chronic and self-perpetuating, regardless of whether the borrelia bacterium is still present in the host, or in the absence of the inciting pathogen in an autoimmune pattern.[58]

References

  1. ↑ Bunikis J, Garpmo U, Tsao J, Berglund J, Fish D, Barbour AG (2004). "Sequence typing reveals extensive strain diversity of the Lyme borreliosis agents Borrelia burgdorferi in North America and Borrelia afzelii in Europe" (PDF). Microbiology. 150 (Pt 6): 1741–55. PMID 15184561.
  2. ↑ Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed. ed.). McGraw Hill. ISBN 0-8385-8529-9.
  3. ↑ Felsenfeld O (1971). Borrelia: Strains, Vectors, Human and Animal Borreliosis. St. Louis: Warren H. Green, Inc.
  4. ↑ Wang G, van Dam AP, Le Fleche A; et al. (1997). "Genetic and phenotypic analysis of Borrelia valaisiana sp. nov. (Borrelia genomic groups VS116 and M19)". Int. J. Syst. Bacteriol. 47 (4): 926–32. PMID 9336888.
  5. ↑ Diza E, Papa A, Vezyri E, Tsounis S, Milonas I, Antoniadis A (2004). "Borrelia valaisiana in cerebrospinal fluid". Emerging Infect. Dis. 10 (9): 1692–3. PMID 15503409.
  6. ↑ Masuzawa T (2004). "Terrestrial distribution of the Lyme borreliosis agent Borrelia burgdorferi sensu lato in East Asia". Jpn. J. Infect. Dis. 57 (6): 229–35. PMID 15623946.
  7. ↑ Collares-Pereira M, Couceiro S, Franca I, Kurtenbach K, Schafer SM, Vitorino L, Goncalves L, Baptista S, Vieira ML, Cunha C (2004). "First isolation of Borrelia lusitaniae from a human patient" (PDF). J Clin Microbiol. 42 (3): 1316–8. PMID 15004107.
  8. ↑ Postic D, Ras NM, Lane RS, Hendson M, Baranton G (1998). "Expanded diversity among Californian borrelia isolates and description of Borrelia bissettii sp. nov. (formerly Borrelia group DN127)" (PDF). J Clin Microbiol. 36 (12): 3497–504. PMID 9817861.
  9. ↑ Maraspin V, Cimperman J, Lotric-Furlan S, Ruzic-Sabljic E, Jurca T, Picken RN, Strle F (2002). "Solitary borrelial lymphocytoma in adult patients". Wien Klin Wochenschr. 114 (13–14): 515–23. PMID 12422593.
  10. ↑ Richter D, Postic D, Sertour N, Livey I, Matuschka FR, Baranton G (2006). "Delineation of Borrelia burgdorferi sensu lato species by multilocus sequence analysis and confirmation of the delineation of Borrelia spielmanii sp. nov". Int J Syst Evol Microbiol. 56 (Pt 4): 873–81. PMID 16585709.
  11. ↑ Foldvari G, Farkas R, Lakos A (2005). "Borrelia spielmanii erythema migrans, Hungary". Emerg Infect Dis. 11 (11): 1794–5. PMID 16422006.
  12. ↑ Scoles GA, Papero M, Beati L, Fish D (2001). "A relapsing fever group spirochete transmitted by Ixodes scapularis ticks". Vector Borne Zoonotic Dis. 1 (1): 21–34. PMID 12653133.
  13. ↑ Bunikis J, Tsao J, Garpmo U, Berglund J, Fish D, Barbour AG (2004). "Typing of Borrelia relapsing fever group strains". Emerg Infect Dis. 10 (9): 1661–4. PMID 15498172.
  14. ↑ Varela AS, Luttrell MP, Howerth EW, Moore VA, Davidson WR, Stallknecht DE, Little SE (2004). "First culture isolation of Borrelia lonestari, putative agent of southern tick-associated rash illness" (PDF). J Clin Microbiol. 42 (3): 1163–9. PMID 15004069.
  15. ↑ Masters E, Granter S, Duray P, Cordes P (1998). "Physician-diagnosed erythema migrans and erythema migrans-like rashes following Lone Star tick bites". Arch Dermatol. 134 (8): 955–60. PMID 9722725.
  16. ↑ Porcella SF, Schwan TG (2001). "Borrelia burgdorferi and Treponema pallidum: a comparison of functional genomics, environmental adaptations, and pathogenic mechanisms". J Clin Invest. 107 (6): 651–6. PMID 11254661.
  17. ↑ Casjens S, Palmer N, van Vugt R, Huang WM, Stevenson B, Rosa P, Lathigra R, Sutton G, Peterson J, Dodson RJ, Haft D, Hickey E, Gwinn M, White O, Fraser CM (2000). "A bacterial genome in flux: the twelve linear and nine circular extrachromosomal DNAs in an infectious isolate of the Lyme disease spirochete Borrelia burgdorferi". Mol Microbiol. 35 (3): 490–516. PMID 10672174.
  18. ↑ Qiu WG, Schutzer SE, Bruno JF, Attie O, Xu Y, Dunn JJ, Fraser CM, Casjens SR, Luft BJ (2004). "Genetic exchange and plasmid transfers in Borrelia burgdorferi sensu stricto revealed by three-way genome comparisons and multilocus sequence typing" (PDF). Proc Natl Acad Sci U S A. 101 (39): 14150–5. PMID 15375210.
  19. ↑ [1]K. "Lyme borreliosis: review of present knowledge" Cesk Epidemiol Mikrobiol Imunol. 1993 Jun;42(2):87-92.
  20. ↑ Bayer ME, Zhang L, Bayer MH (1996). "Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms. A PCR study of 97 cases". Infection. 24 (5): 347–53. PMID 8923044.
  21. ↑ Preac-Mursic V, Weber K, Pfister HW; et al. (1989). "Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis". Infection. 17 (6): 355–9. PMID 2613324.
  22. ↑ Oksi J, Marjamaki M, Nikoskelainen J, Viljanen MK (1999). "Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis". Ann Med. 31 (3): 225–32. PMID 10442678.
  23. ↑ 23.0 23.1 23.2 Embers ME, Ramamoorthy R, Philipp MT (2004). "Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease". Microbes Infect. 6 (3): 312–8. PMID 15065567.
  24. ↑ Miklossy J, Khalili K, Gern L; et al. (2004). "Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease". J Alzheimers Dis. 6 (6): 639–49, discussion 673-81. PMID 15665404.
  25. ↑ Grab DJ, Perides G, Dumler JS, Kim KJ, Park J, Kim YV, Nikolskaia O, Choi KS, Stins MF, Kim KS (2005). "Borrelia burgdorferi, host-derived proteases, and the blood-brain barrier". Infect Immun. 73 (2): 1014–22. PMID 15664945.
  26. ↑ Ma Y, Sturrock A, Weis JJ (1991). "Intracellular localization of Borrelia burgdorferi within human endothelial cells" (PDF). Infect Immun. 59 (2): 671–8. PMID 1987083.
  27. ↑ Klempner MS, Noring R, Rogers RA (1993). "Invasion of human skin fibroblasts by the Lyme disease spirochete, Borrelia burgdorferi". J Infect Dis. 167 (5): 1074–81. PMID 8486939.
  28. ↑ Dorward DW, Fischer ER, Brooks DM (1997). "Invasion and cytopathic killing of human lymphocytes by spirochetes causing Lyme disease". Clin Infect Dis. 25 Suppl 1: S2–8. PMID 9233657.
  29. ↑ Montgomery RR, Nathanson MH, Malawista SE (1993). "The fate of Borrelia burgdorferi, the agent for Lyme disease, in mouse macrophages. Destruction, survival, recovery". J Immunol. 150 (3): 909–15. PMID 8423346.
  30. ↑ Aberer E, Kersten A, Klade H, Poitschek C, Jurecka W (1996). "Heterogeneity of Borrelia burgdorferi in the skin". Am J Dermatopathol. 18 (6): 571–9. PMID 8989928.
  31. ↑ Girschick HJ, Huppertz HI, Russmann H, Krenn V, Karch H (1996). "Intracellular persistence of Borrelia burgdorferi in human synovial cells". Rheumatol Int. 16 (3): 125–32. PMID 8893378.
  32. ↑ 32.0 32.1 Nanagara R, Duray PH, Schumacher HR Jr (1996). "Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic Lyme disease: possible factors contributing to persistence of organisms". Hum Pathol. 27 (10): 1025–34. PMID 8892586.
  33. ↑ Livengood JA, Gilmore RD (2006). "Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi". Microbes Infect. [Epub ahead of print]. PMID 17045505.
  34. ↑ Georgilis K, Peacocke M, Klempner MS (1992). "Fibroblasts protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro". J Infect Dis. 166 (2): 440–4. PMID 1634816.
  35. ↑ Brouqui P, Badiaga S, Raoult D (1996). "Eucaryotic cells protect Borrelia burgdorferi from the action of penicillin and ceftriaxone but not from the action of doxycycline and erythromycin" (PDF). Antimicrob Agents Chemother. 40 (6): 1552–4. PMID 8726038.
  36. ↑ 36.0 36.1 Alban PS, Johnson PW, Nelson DR (2000). "Serum-starvation-induced changes in protein synthesis and morphology of Borrelia burgdorferi". Microbiology. 146 ( Pt 1): 119–27. PMID 10658658.
  37. ↑ 37.0 37.1 Mursic VP, Wanner G, Reinhardt S; et al. (1996). "Formation and cultivation of Borrelia burgdorferi spheroplast-L-form variants". Infection. 24 (3): 218–26. PMID 8811359.
  38. ↑ Kersten A, Poitschek C, Rauch S, Aberer E (1995). "Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi" (PDF). Antimicrob Agents Chemother. 39 (5): 1127–33. PMID 7625800.
  39. ↑ Schaller M, Neubert U (1994). "Ultrastructure of Borrelia burgdorferi after exposure to benzylpenicillin". Infection. 22 (6): 401–6. PMID 7698837.
  40. ↑ Phillips SE, Mattman LH, Hulinska D, Moayad H (1998). "A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated". Infection. 26 (6): 364–7. PMID 9861561.
  41. ↑ Duray PH, Yin SR, Ito Y; et al. (2005). "Invasion of human tissue ex vivo by Borrelia burgdorferi". J Infect Dis. 191 (10): 1747–54. PMID 15838803.
  42. ↑ Gruntar I, Malovrh T, Murgia R, Cinco M (2001). "Conversion of Borrelia garinii cystic forms to motile spirochetes in vivo". APMIS. 109 (5): 383–8. PMID 11478686.
  43. ↑ Murgia R, Cinco M (2004). "Induction of cystic forms by different stress conditions in Borrelia burgdorferi". APMIS. 112 (1): 57–62. PMID 14961976.
  44. ↑ Brorson O, Brorson SH (1999). "An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to metronidazole". APMIS. 107 (6): 566–76. PMID 10379684.
  45. ↑ Brorson O, Brorson SH (2004). "An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to tinidazole" (PDF). Int Microbiol. 7 (2): 139–42. PMID 15248163.
  46. ↑ Brorson O, Brorson SH (2002). "An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to hydroxychloroquine". Int Microbiol. 5 (1): 25–31. PMID 12102233.
  47. ↑ Liang FT, Yan J, Mbow ML; et al. (2004). "Borrelia burgdorferi changes its surface antigenic expression in response to host immune responses". Infect Immun. 72 (10): 5759–67. PMID 15385475.
  48. ↑ Gilmore RD, Howison RR, Schmit VL; et al. (2007). "Temporal expression analysis of the Borrelia burgdorferi paralogous gene family 54 genes BBA64, BBA65, and BBA66 during persistent infection in mice". Infect. Immun. 75 (6): 2753–64. doi:10.1128/IAI.00037-07. PMID 17371862.
  49. ↑ Schutzer SE, Coyle PK, Reid P, Holland B (1999). "Borrelia burgdorferi-specific immune complexes in acute Lyme disease". JAMA. 282 (20): 1942–6. PMID 10580460.
  50. ↑ Newman K Jr, Johnson RC."T-cell-independent elimination of Borrelia turicatae".Infect Immun. 1984 Sep;45(3):572-6.
  51. ↑ Dattwyler RJ, Thomas JA, Benach JL, Golightly MG."Cellular immune response in Lyme disease: the response to mitogens, live Borrelia burgdorferi, NK cell function and lymphocyte subsets". Zentralbl Bakteriol Mikrobiol Hyg [A]. 1986 Dec;263(1-2):151-9
  52. ↑ Kruger H, Pulz M, Martin R, Sticht-Groh V. "Long-term persistence of specific T- and B-lymphocyte responses to Borrelia burgdorferi following untreated neuroborreliosis". Infection. 1990 Sep-Oct;18(5):263-7.
  53. ↑ Forsberg P, Ernerudh J, Ekerfelt C, Roberg M, Vrethem M, Bergstrom S. "The outer surface proteins of Lyme disease borrelia spirochetes stimulate T cells to secrete interferon-gamma (IFN-gamma): diagnostic and pathogenic implications". Clin Exp Immunol. 1995 Sep;101(3):453-60.
  54. ↑ Yin Z, Braun J, Neure L, Wu P, Eggens U, Krause A, Kamradt T, Sieper J. "T cell cytokine pattern in the joints of patients with Lyme arthritis and its regulation by cytokines and anticytokines". Arthritis Rheum. 1997 Jan;40(1):69-79.
  55. ↑ Jarefors S, Janefjord CK, Forsberg P, Jenmalm MC, Ekerfelt C. "Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic Borrelia-exposed individuals." Clin Exp Immunol. 2007 Jan;147(1):18-27
  56. ↑ Olson CM, Hedrick MN, Izadi H, Bates TC, Olivera ER, Anguita J. "p38 mitogen-activated protein kinase controls NF-kappaB transcriptional activation and tumor necrosis factor alpha production through RelA phosphorylation mediated by mitogen- and stress-activated protein kinase 1 in response to Borrelia burgdorferi antigens." Infect Immun. 2007 Jan;75(1):270-7. Epub 2006 Oct 30.
  57. ↑ Ramesh G, Philipp MT. "Pathogenesis of Lyme neuroborreliosis: mitogen-activated protein kinases Erk1, Erk2, and p38 in the response of astrocytes to Borrelia burgdorferi lipoproteins". Neurosci Lett. 2005 Aug 12-19;384(1-2):112-6
  58. ↑ Singh SK, Girschick HJ (2006). "Toll-like receptors in Borrelia burgdorferi-induced inflammation". Clin. Microbiol. Infect. 12 (8): 705–17. doi:10.1111/j.1469-0691.2006.01440.x. PMID 16842565.

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