Review Article | Published:

Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes

Nature Reviews Microbiology volume 10, pages 8799 (2012) | Download Citation

Abstract

In little more than 30 years, Lyme disease, which is caused by the spirochaete Borrelia burgdorferi, has risen from relative obscurity to become a global public health problem and a prototype of an emerging infection. During this period, there has been an extraordinary accumulation of knowledge on the phylogenetic diversity, molecular biology, genetics and host interactions of B. burgdorferi. In this Review, we integrate this large body of information into a cohesive picture of the molecular and cellular events that transpire as Lyme disease spirochaetes transit between their arthropod and vertebrate hosts during the enzootic cycle.

Key points

  • Lyme disease first came to public attention in the 1970s as a result of an epidemic of oligoarthritis in children and adults living in the vicinity of the town of Lyme, Connecticut, USA. The observation that infected individuals had a skin lesion called erythema migrans was crucial to identifying the causative agent (the spirochaete Borrelia burgdorferi) and its arthropod vector (Ixodes scapularis).Lyme disease is now known to be worldwide in distribution and is a major public health problem in the United States.

  • B. burgdorferi is perpetuated in an enzootic cycle in which uninfected larval ticks acquire the spirochaete by feeding on an infected reservoir host, usually a small mammal (for example, the white-footed mouse, Peromyscus leucopus). The infected larvae moult to become nymphs, which then transmit the bacterium to an uninfected animal with the next blood meal. The outcome of infection is variable and dependent on the mammalian host. Humans are an incidental, dead-end host.

  • B. burgdorferi has an unusual genome consisting of a 1 Mb linear chromosome and numerous linear and circular plasmids. The plasmids are a primary repository for differentially expressed lipoproteins. The bacterium is an auxotroph for all amino acids, nucleotides and fatty acids; it also lacks genes encoding enzymes for the tricarboxylic acid cycle and oxidative phosphorylation.

  • B. burgdorferi resembles a Gram-negative bacterium in that it contains both outer and inner membranes. However, the architecture and composition of its outer membrane differ markedly from those of Gram-negative bacteria. Most notably, decorating the surface of B. burgdorferi are differentially expressed outer-surface lipoproteins. As with all spirochaetes, the organelles of motility (the flagella) are located in the periplasmic space.

  • With the onset of the nymphal blood meal, spirochaetes in flat nymphal ticks undergo extensive changes in gene and protein expression that enable transmission of B. burgdorferi to the mammalian host. Many of these transcriptional changes are regulated by the response regulatory protein 2 (Rrp2)–RpoN–RpoS and histidine kinase Hk1–Rrp1 pathways.

  • Following transmission, borrelial virulence determinants (for example, OspC) act in concert with tick salivary components (SALPs) to enable the bacterium to establish a foothold at the bite site and subsequently disseminate.

  • The presence of spirochaetes locally and in tissues following dissemination triggers innate immune pathogen-sensing mechanisms (for example, Toll-like receptors), which recruit circulating leukocytes and orchestrate the development of the adaptive response. Macrophages are thought to be crucial innate immune effectors for bacterial clearance.

  • Clearance of organisms is dependent on the appearance of specific antibodies. Spirochaetes counter the humoral response of the host by downregulating target surface antigens and activating the recombinatorial surface lipoprotein system (vls) for antigenic variation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & in Borrelia: Molecular Biology, Host Interaction, and Pathogenesis (eds Samuels, D. S. & Radolf, J. D.) 7–26 (Caister Academic, Norfolk, UK, 2010).

  2. 2.

    et al. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum. 20, 7–17 (1977). An article describing the original epidemiological study of the outbreak of arthritis in and around Lyme, Connecticut.

  3. 3.

    et al. Lyme disease—a tick-borne spirochetosis? Science 216, 1317–1319 (1982). A classic paper that provides the first convincing evidence that Lyme disease is a tick-borne illness.

  4. 4.

    et al. The spirochetal etiology of Lyme disease. N. Engl. J. Med. 308, 733–740 (1983).

  5. 5.

    et al. Spirochetes isolated from the blood of two patients with Lyme disease. N. Engl. J. Med. 308, 740–742 (1983). This and reference 4 are the first two reports to describe the isolation of Lyme disease spirochaetes from patients.

  6. 6.

    & Genetic relationship of Lyme disease spirochetes to Borrelia, Treponema, and Leptospira spp. J. Clin. Microbiol. 20, 151–154 (1984).

  7. 7.

    & in Borrelia: Molecular Biology, Host Interaction, and Pathogenesis (eds Samuels, D. S. & Radolf, J. D.) 251–278 (Caister Academic, Norfolk, UK, 2010).

  8. 8.

    et al. Summary of notifiable diseases — United States, 2008. Morb. Mortal. Wkly Rep. 57, 1–94 (2010).

  9. 9.

    , , & Epidemiology of European Lyme borreliosis. Zentralbl. Bakteriol. 287, 229–240 (1998).

  10. 10.

    et al. Fundamental processes in the evolutionary ecology of Lyme borreliosis. Nature Rev. Microbiol. 4, 660–669 (2006).

  11. 11.

    & Intrinsic competence of three ixodid ticks (Acari) as vectors of the Lyme disease spirochete. J. Med. Entomol. 27, 646–650 (1990).

  12. 12.

    , , & Dissemination and salivary delivery of Lyme disease spirochetes in vector ticks (Acari: Ixodidae). J. Med. Entomol. 24, 201–205 (1987). A definitive demonstration that spirochaetes are transmitted by the salivary route during tick feeding.

  13. 13.

    , , & Duration of tick attachment and Borrelia burgdorferi transmission. J. Clin. Microbiol. 25, 557–558 (1987). A classic study that defines the 48 hour window required for transmission of spirochaetes by feeding nymphs.

  14. 14.

    , & in Borrelia: Molecular Biology, Host Interaction, and Pathogenesis (eds Samuels, D. S. & Radolf, J. D.) 359–411 (Caister Academic, Norfolk, UK, 2010).

  15. 15.

    & in Borrelia: Molecular Biology, Host Interaction, and Pathogenesis (ed. Samuels, D. S. & Radolf, J. D.) 413–441 (Caister Academic, Norfolk, UK, 2010).

  16. 16.

    et al. Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature 390, 580–586 (1997). A sequence analysis of the B. burgdorferi chromosome; one of the first genomic-sequence papers for this species.

  17. 17.

    , & in Borrelia: Molecular Biology, Host Interaction, and Pathogenesis (eds Samuels, D. S. & Radolf, J. D.) 487–533 (Caister Academic, Norfolk, UK, 2010).

  18. 18.

    et al. The prevalence and incidence of clinical and asymptomatic Lyme borreliosis in a population at risk. J. Infect. Dis. 163, 305–310 (1991).

  19. 19.

    et al. Brief communication: hematogenous dissemination in early Lyme disease. Ann. Intern. Med. 142, 751–755 (2005).

  20. 20.

    & Lyme disease: European perspective. Infect. Dis. Clin. North Am. 22, 327–339, (2008).

  21. 21.

    et al. Borrelia burgdorferi genotype predicts the capacity for hematogenous dissemination during early Lyme disease. J. Infect. Dis. 198, 1358–1364 (2008).

  22. 22.

    , , & Demonstration of OspC type diversity in invasive human Lyme disease isolates and identification of previously uncharacterized epitopes that define the specificity of the OspC murine antibody response. Infect. Immun. 73, 7869–7877 (2005).

  23. 23.

    , & in Borrelia: Molecular Biology, Host Interaction, and Pathogenesis (eds Samuels, D. S. & Radolf, J. D.) 27–53 (Caister Academic, Norfolk, UK, 2010).

  24. 24.

    , , & in Borrelia: Molecular Biology, Host Interaction, and Pathogenesis (eds Samuels, D. S. & Radolf, J. D.) 103–138 (Caister Academic, Norfolk, UK, 2010).

  25. 25.

    & Carbohydrate utilization by the Lyme borreliosis spirochete, Borrelia burgdorferi. FEMS Microbiol. Lett. 243, 173–179 (2005).

  26. 26.

    & Lack of a role for iron in the Lyme disease pathogen. Science 288, 1651–1653 (2000). An article that provides evidence for one of the most unusual physiological properties of B. burgdorferi: its lack of a requirement for iron.

  27. 27.

    et al. The Lyme disease agent Borrelia burgdorferi requires BB0690, a Dps homologue, to persist within ticks. Mol. Microbiol. 63, 694–710 (2007).

  28. 28.

    & in Borrelia: Molecular Biology, Host Interaction, and Pathogenesis (eds Samuels, D. S. & Radolf, J. D.) 139–166 (Caister Academic, Norfolk, UK, 2010).

  29. 29.

    et al. Cholesterol lipids of Borrelia burgdorferi form lipid rafts and are required for the bactericidal activity of a complement-independent antibody. Cell Host Microbe 8, 331–342 (2010). A technically innovative study relating antibody killing of spirochaetes to the unique lipid composition and physical properties of the spirochaete outer membrane.

  30. 30.

    et al. Acylated cholesteryl galactoside as a novel immunogenic motif in Borrelia burgdorferi sensu stricto. J. Biol. Chem. 278, 33645–33653 (2003).

  31. 31.

    et al. An RND-type efflux system in Borrelia burgdorferi is involved in virulence and resistance to antimicrobial compounds. PLoS Pathog. 4, e1000009 (2008).

  32. 32.

    & Borrelia burgdorferi locus BB0795 encodes a BamA orthologue required for growth and efficient localization of outer membrane proteins. Mol. Microbiol. 75, 692–709 (2010).

  33. 33.

    et al. in Borrelia: Molecular Biology, Host Interaction, and Pathogenesis (eds Samuels, D. S. & Radolf, J. D.) 167–187 (Caister Academic, Norfolk, UK, 2010).

  34. 34.

    et al. Intact flagellar motor of Borrelia burgdorferi revealed by cryo-electron tomography: evidence for stator ring curvature and rotor/C-ring assembly flexion. J. Bacteriol. 191, 5026–5036 (2009).

  35. 35.

    et al. The flat-ribbon configuration of the periplasmic flagella of Borrelia burgdorferi and its relationship to motility and morphology. J. Bacteriol. 191, 600–607 (2009).

  36. 36.

    , , , & Chemoreceptors and flagellar motors are subterminally located in close proximity at the two cell poles in spirochetes. J. Bacteriol. 193, 2652–2656 (2011).

  37. 37.

    , , , & in Borrelia: Molecular Biology, Host Interaction, and Pathogenesis (eds Samuels, D. S. & Radolf, J. D.) 67–101 (Caister Academic, Norfolk, UK, 2010).

  38. 38.

    Gene regulation in Borrelia burgdorferi. Annu. Rev. Microbiol. 65, 479–499 (2011).

  39. 39.

    et al. Expression of Borrelia burgdorferi OspC and DbpA is controlled by a RpoN–RpoS regulatory pathway. Proc. Natl Acad. Sci. USA 98, 12724–12729 (2001). A ground-breaking demonstration of the unique control mechanism for rpoS transcription in B. burgdorferi and the role of this alternative σ-factor in controlling virulence gene expression.

  40. 40.

    et al. Borrelia burgdorferi σ54 is required for mammalian infection and vector transmission but not for tick colonization. Proc. Natl Acad. Sci. USA 102, 5162–5167 (2005).

  41. 41.

    et al. Analysis of the RpoS regulon in Borrelia burgdorferi in response to mammalian host signals provides insight into RpoS function during the enzootic cycle. Mol. Microbiol. 65, 1193–1217 (2007).

  42. 42.

    , & The response regulator Rrp2 is essential for the expression of major membrane lipoproteins in Borrelia burgdorferi. Proc. Natl Acad. Sci. USA 100, 11001–11006 (2003). An elegant use of mutagenesis to demonstrate the essentiality of Rrp2 for the induction of RpoS-dependent gene regulation.

  43. 43.

    et al. Rrp2, a σ54-dependent transcriptional activator of Borrelia burgdorferi, activates rpoS in an enhancer-independent manner. J. Bacteriol. 191, 2902–2905 (2009).

  44. 44.

    et al. Essential role of the response regulator Rrp2 in the infectious cycle of Borrelia burgdorferi. Infect. Immun. 76, 3844–3853 (2008).

  45. 45.

    et al. Insights into the complex regulation of rpoS in Borrelia burgdorferi. Mol. Microbiol. 65, 277–293 (2007).

  46. 46.

    , , , & The BosR regulatory protein of Borrelia burgdorferi interfaces with the RpoS regulatory pathway and modulates both the oxidative stress response and pathogenic properties of the Lyme disease spirochete. Mol. Microbiol. 74, 1344–1355 (2009). One of the first investigations to demonstrate that the borrelial Fur–PerR orthologue, BosR, is required for expression of rpoS.

  47. 47.

    , & BosR (BB0647) controls the RpoN-RpoS regulatory pathway and virulence expression in Borrelia burgdorferi by a novel DNA-binding mechanism. PLoS Pathog. 7, e1001272 (2011). An impressive work that defines the binding-site motif for BosR near the rpoS promoter.

  48. 48.

    et al. Role of acetyl-phosphate in activation of the Rrp2-RpoN-RpoS pathway in Borrelia burgdorferi. PLoS Pathog. 6, e1001104 (2010). A study that elegantly relates the concept of the acetate switch in E. coli to the activation of Rrp2 and differential gene expression in B. burgdorferi.

  49. 49.

    & Temperature-induced regulation of RpoS by a small RNA in Borrelia burgdorferi. Mol. Microbiol. 64, 1075–1089 (2007). The first paper to present evidence for post-transcriptional regulation of rpoS in B. burgdorferi.

  50. 50.

    , , & Identification and function of the RNA chaperone Hfq in the Lyme disease spirochete Borrelia burgdorferi. Mol. Microbiol. 78, 622–635 (2010).

  51. 51.

    et al. CsrA modulates levels of lipoproteins and key regulators of gene expression critical for pathogenic mechanisms of Borrelia burgdorferi. Infect. Immun. 79, 732–744 (2011).

  52. 52.

    & Inactivation of bb0184, which encodes carbon storage regulator A, represses the infectivity of Borrelia burgdorferi. Infect. Immun. 79, 1270–1279 (2011).

  53. 53.

    et al. BpaB and EbfC DNA-binding proteins regulate production of the Lyme disease spirochete's infection-associated Erp surface proteins. J. Bacteriol. 9 Dec 2011 (doi:10.1128/JB.06394-11).

  54. 54.

    et al. Regulators of expression of the oligopeptide permease A proteins of Borrelia burgdorferi. J. Bacteriol. 189, 2653–2659 (2007).

  55. 55.

    , , & Interaction of Borrelia burgdorferi Hbb with the p66 promoter. Nucleic Acids Res. 38, 414–427 (2010).

  56. 56.

    et al. The hybrid histidine kinase Hk1 is part of a two-component system that is essential for survival of Borrelia burgdorferi in feeding Ixodes scapularis ticks. Infect. Immun. 79, 3117–3130 (2011). The demonstration that the sensor kinase Hk1 is required for adaptation of the spirochaete to the tick host.

  57. 57.

    et al. Cyclic di-GMP is essential for the survival of Borrelia burgdorferi in ticks. PLOS Pathog. 7, e1002133 (2011). The discovery that the response regulator Rrp1 is required for adaptation of the spirochaete to the tick host.

  58. 58.

    et al. The diguanylate cyclase, Rrp1, regulates critical steps in the enzootic cycle of the Lyme disease spirochetes. Mol. Microbiol. 81, 219–231 (2011). The finding that Rrp1 is required for adaptation of the spirochaete to the tick host.

  59. 59.

    et al. Analysis of the HD-GYP domain cyclic-di-GMP phosphodiesterase reveals a role in motility and enzootic life cycle of Borrelia burgdorferi. Infect. Immun. 79, 3273–3283 (2011).

  60. 60.

    , , & Analysis of a Borrelia burgdorferi phosphodiesterase demonstrates a role for cyclic-di-guanosine monophosphate in motility and virulence. Mol. Microbiol. 77, 128–142 (2010).

  61. 61.

    et al. Real-time high resolution 3D imaging of the Lyme disease spirochete adhering to and escaping from the vasculature of a living host. PLoS Pathog. 4, e1000090 (2008). A landmark paper describing in vivo imaging of B. burgdorferi in mice, including remarkable images and movies of spirochaetes penetrating the vascular endothelium.

  62. 62.

    & Temporal changes in outer surface proteins A and C of the Lyme disease-associated spirochete, Borrelia burgdorferi, during the chain of infection in ticks and mice. J. Clin. Microbiol. 38, 382–388 (2000).

  63. 63.

    et al. Borrelia burgdorferi bba74 is expressed exclusively during tick feeding and is regulated by both arthropod- and mammalian host-specific signals. J. Bacteriol. 191, 2783–2794 (2009).

  64. 64.

    , , & Borrelia burgdorferi intercepts host hormonal signals to regulate expression of outer surface protein A. Proc. Natl Acad. Sci. USA 104, 7247–7252 (2007).

  65. 65.

    et al. TROSPA, an Ixodes scapularis receptor for Borrelia burgdorferi. Cell 119, 457–468 (2004). The identification of the receptor, expressed on tick midgut epithelial cells, that is crucial for the tick phase of the spirochaete's enzootic life cycle.

  66. 66.

    , , , & Essential role for OspA/B in the life cycle of the Lyme disease spirochete. J. Exp. Med. 199, 641–648 (2004). An elegant genetic demonstration that spirochaetes lacking OspA are virulent but unable to colonize larval midguts.

  67. 67.

    et al. Outer surface protein A protects Lyme disease spirochetes from acquired host immunity in the tick vector. Infect. Immun. 76, 5228–5237 (2008).

  68. 68.

    & in Borrelia: Molecular Biology, Host Interactions, and Pathogenesis (eds Samuels, D. S. & Radolf, J. D.) 279–298 (Caister Academic, Norfold, UK, 2010).

  69. 69.

    et al. Borrelia burgdorferi requires glycerol for maximum fitness during the tick phase of the enzootic cycle. PLoS Pathog. 7, e1002102 (2011).

  70. 70.

    et al. Genetics and regulation of chitobiose utilization in Borrelia burgdorferi. J. Bacteriol. 183, 5544–5553 (2001).

  71. 71.

    et al. Live imaging reveals a biphasic mode of dissemination of Borrelia burgdorferi within ticks. J. Clin. Invest. 119, 3652–3665 (2009). The first paper to use live imaging to track spirochaetes disseminating in feeding nymphs.

  72. 72.

    , & DNA microarray analysis of differential gene expression in Borrelia burgdorferi, the Lyme disease spirochete. Proc. Natl Acad. Sci. USA 99, 1562–1567 (2002). The first microarray analysis of the B. burgdorferi transcriptome, which cleverly uses in vitro conditions to emulate the tick and mammalian phases of the enzootic cycle.

  73. 73.

    et al. Profiling of temperature-induced changes in Borrelia burgdorferi gene expression by using whole genome arrays. Infect. Immun. 71, 1689–1705 (2003).

  74. 74.

    , , & Combined effects of blood and temperature shift on Borrelia burgdorferi gene expression as determined by whole genome DNA array. Infect. Immun. 72, 5419–5432 (2004).

  75. 75.

    et al. bptA (bbe16) is essential for the persistence of the Lyme disease spirochete, Borrelia burgdorferi, in its natural tick vector. Proc. Natl Acad. Sci. USA 102, 6972–6977 (2005).

  76. 76.

    , , , & Induction of an outer surface protein on Borrelia burgdorferi during tick feeding. Proc. Natl Acad. Sci. USA 92, 2909–2913 (1995). The seminal demonstration of the induction of OspC during the nymphal blood meal and the importance of temperature as a stimulus for differential gene expression.

  77. 77.

    , & Use of quantitative PCR to measure density of Borrelia burgdorferi in the midgut and salivary glands of feeding tick vectors. J. Clin. Microbiol. 39, 4145–4148 (2001).

  78. 78.

    & Targeted mutation of the outer membrane protein P66 disrupts attachment of the Lyme disease agent, Borrelia burgdorferi, to integrin αVβ3. Proc. Natl Acad. Sci. USA 100, 7301–7306 (2003). The first report to use targeted mutagenesis to show that a borrelial outer-membrane-spanning protein has a role in cytoadherence.

  79. 79.

    et al. Elimination of channel-forming activity by insertional inactivation of the p66 gene in Borrelia burgdorferi. FEMS Microbiol. Lett. 266, 241–249 (2007).

  80. 80.

    , , , & in Borrelia: Molecular Biology, Host Interaction, and Pathogenesis (eds Samuels, D. S. & Radolf, J. D.) 299–331 (Caister Academic, Norfolk, UK, 2010).

  81. 81.

    et al. The complement regulator factor H binds to the surface protein OspE of Borrelia burgdorferi. J. Biol. Chem. 276, 8427–8435 (2001).

  82. 82.

    & The OspE-related proteins inhibit complement deposition and enhance serum resistance of Borrelia burgdorferi, the Lyme disease spirochete. Infect. Immun. 79, 1451–1457 (2011).

  83. 83.

    , , , & Differential binding of host complement inhibitor factor H by Borrelia burgdorferi Erp surface proteins: a possible mechanism underlying the expansive host range of Lyme disease spirochetes. Infect. Immun. 70, 491–497 (2002).

  84. 84.

    et al. Complement resistance of Borrelia burgdorferi correlates with the expression of BbCRASP-1, a novel linear plasmid-encoded surface protein that interacts with human factor H and FHL-1 and is unrelated to Erp proteins. J. Biol. Chem. 279, 2421–2429 (2004).

  85. 85.

    et al. Complement factor H-related proteins CFHR2 and CFHR5 represent novel ligands for the infection-associated CRASP proteins of Borrelia burgdorferi. PLoS ONE 5, e13519 (2010).

  86. 86.

    & Growth and migration of Borrelia burgdorferi in Ixodes ticks during blood feeding. Am. J. Trop. Med. Hyg. 53, 397–404 (1995). A detailed analysis of the route of spirochaete dissemination and the kinetics of spirochaete replication during the nymphal blood meal; this paper also provides additional evidence for salivary transmission of spirochaetes.

  87. 87.

    , & Antigenic and genetic heterogeneity of Borrelia burgdorferi populations transmitted by ticks. Proc. Natl Acad. Sci. USA 98, 670–675 (2001). A meticulous characterization of the expression profiles of OspA and OspC during tick dissemination.

  88. 88.

    et al. Plasminogen is required for efficient dissemination of B. burgdorferi in ticks and for enhancement of spirochetemia in mice. Cell 89, 1111–1119 (1997). A classic demonstration of how B. burgdorferi appropriates mammalian serum proteins to facilitate penetration of tick tissue barriers.

  89. 89.

    et al. Molecular interactions that enable movement of the Lyme disease agent from the tick gut into the hemolymph. PLoS Pathog. 7, e1002079 (2011).

  90. 90.

    et al. Borrelia burgdorferi binds plasminogen, resulting in enhanced penetration of endothelial monolayers. Infect. Immun. 63, 2478–2484 (1995).

  91. 91.

    et al. Inhibition of neutrophil function by two tick salivary proteins. Infect. Immun. 77, 2320–2329 (2009).

  92. 92.

    et al. Antiinflammatory and immunosuppressive activity of sialostatin L, a salivary cystatin from the tick Ixodes scapularis. J. Biol. Chem. 281, 26298–26307 (2006).

  93. 93.

    et al. The Lyme disease agent exploits a tick protein to infect the mammalian host. Nature 436, 573–577 (2005).

  94. 94.

    et al. OspC facilitates Borrelia burgdorferi invasion of Ixodes scapularis salivary glands. J. Clin. Invest. 113, 220–230 (2004).

  95. 95.

    et al. Outer-surface protein C of the Lyme disease spirochete: a protein induced in ticks for infection of mammals. Proc. Natl Acad. Sci. USA 101, 3142–3147 (2004). A definitive demonstration that OspC is a borrelial virulence determinant following infection of mammals via needle or tick.

  96. 96.

    et al. Borrelia burgdorferi OspC protein required exclusively in a crucial early stage of mammalian infection. Infect. Immun. 74, 3554–3564 (2006).

  97. 97.

    , , , & Recognition of Borrelia burgdorferi, the Lyme disease spirochete, by TLR7 and TLR9 induces a type I IFN response by human immune cells. J. Immunol. 183, 5279–5292 (2009). The first report to show that borreliae activate host immune responsesvia endosomal TLRs.

  98. 98.

    et al. Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-β. Proc. Natl Acad. Sci. USA 108, 3683–3688 (2011). A paper confirming B. burgdorferi degradation in phagosomes as the principal mechanism for TLR signalling, and showing TLR2–TLR8 cooperativity.

  99. 99.

    et al. A critical role for type I IFN in arthritis development following Borrelia burgdorferi infection of mice. J. Immunol. 181, 8492–8503 (2008). A landmark paper calling attention to the involvement of type I IFNs in Lyme disease.

  100. 100.

    et al. Distinct roles for MyD88 and Toll-like receptors 2, 5, and 9 in phagocytosis of Borrelia burgdorferi and cytokine induction. Infect. Immun. 76, 2341–2351 (2008).

  101. 101.

    , , , & Human integrin α3β1 regulates TLR2 recognition of lipopeptides from endosomal compartments. PLoS ONE 5, e12871 (2010).

  102. 102.

    et al. Coevolution of markers of innate and adaptive immunity in skin and peripheral blood of patients with erythema migrans. J. Immunol. 171, 2660–2670 (2003).

  103. 103.

    Histopathology of clinical phases of human Lyme disease. Rheum. Dis. Clin. North Am. 15, 691–710 (1989).

  104. 104.

    et al. Higher mRNA levels of chemokines and cytokines associated with macrophage activation in erythema migrans skin lesions in patients from the United States than in patients from Austria with Lyme borreliosis. Clin. Infect. Dis. 46, 85–92 (2008).

  105. 105.

    , , & Delayed dissemination of Lyme disease spirochetes from the site of deposition in the skin of mice. J. Infect. Dis. 166, 827–831 (1992).

  106. 106.

    et al. Borrelia burgdorferi infection-associated surface proteins ErpP, ErpA, and ErpC bind human plasminogen. Infect. Immun. 77, 300–306 (2009).

  107. 107.

    et al. Borrelia burgdorferi BBB07 interaction with integrin α3β1 stimulates production of pro-inflammatory mediators in primary human chondrocytes. Cell. Microbiol. 10, 320–331 (2008).

  108. 108.

    , , & Adherence of Borrelia burgdorferi to the proteoglycan decorin. Infect. Immun. 63, 3467–3472 (1995).

  109. 109.

    , , & Adaptation of the Lyme disease spirochaete to the mammalian host environment results in enhanced glycosaminoglycan and host cell binding. Mol. Microbiol. 47, 1433–1444 (2003).

  110. 110.

    , , , & The Borrelia burgdorferi outer-surface protein ErpX binds mammalian laminin. Microbiology 155, 863–872 (2009).

  111. 111.

    , , & Borrelia burgdorferi BmpA is a laminin-binding protein. Infect. Immun. 77, 4940–4946 (2009).

  112. 112.

    et al. Inactivation of the fibronectin-binding adhesin gene bbk32 significantly attenuates the infectivity potential of Borrelia burgdorferi. Mol. Microbiol. 59, 1591–1601 (2006).

  113. 113.

    , , , & Borrelia burgdorferi RevA antigen binds host fibronectin. Infect. Immun. 77, 2802–2812 (2009).

  114. 114.

    et al. Local production of IFN-γ by invariant NKT cells modulates acute Lyme carditis. J. Immunol. 182, 3728–3734 (2009).

  115. 115.

    , , & Stat1 deficiency exacerbates carditis but not arthritis during experimental Lyme borreliosis. J. Interferon Cytokine Res. 26, 390–399 (2006).

  116. 116.

    et al. Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nature Immunol. 7, 978–986 (2006). A remarkable biochemical and immunological study showing that borrelial glycolipids activate natural killer T cells.

  117. 117.

    et al. An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nature Immunol. 11, 295–302 (2010).

  118. 118.

    , & Cutting edge: T cell-mediated pathology in murine Lyme borreliosis. J. Immunol. 164, 6096–6099 (2000).

  119. 119.

    & The versatile roles of antibodies in Borrelia infections. Nature Rev. Microbiol. 3, 411–420 (2005).

  120. 120.

    , , & Marginal zone B-cell depletion impairs murine host defense against Borrelia burgdorferi infection. Infect. Immun. 75, 3354–3360 (2007).

  121. 121.

    et al. Lymphoadenopathy during Lyme borreliosis is caused by spirochete migration-induced specific B cell activation. PLoS Pathog. 7, e1002066 (2011).

  122. 122.

    et al. Toll-like receptor 2 is required for innate, but not acquired, host defense to Borrelia burgdorferi. J. Immunol. 168, 348–355 (2002).

  123. 123.

    et al. MyD88 plays a unique role in host defense but not arthritis development in Lyme disease. J. Immunol. 173, 2003–2010 (2004).

  124. 124.

    , , & An immune evasion mechanism for spirochetal persistence in Lyme borreliosis. J. Exp. Med. 195, 415–422 (2002). An elegant study demonstrating that OspC-specific antibodies select for spirochaetes that have downregulated expression of the lipoprotein during early mouse infection.

  125. 125.

    , , & Antigenic variation in Lyme disease Borreliae by promiscuous recombination of VMP-like sequence cassettes. Cell 89, 275–285 (1997). The first report to describe the vls system for antigenic variation by B. burgdorferi.

  126. 126.

    Antigenic variation with a twist–the Borrelia story. Mol. Microbiol. 60, 1319–1322 (2006).

  127. 127.

    et al. NOD2 suppresses Borrelia burgdorferi mediated murine Lyme arthritis and carditis through the induction of tolerance. PLoS ONE 6, e17414 (2011).

  128. 128.

    et al. An enzootic transmission cycle of Lyme borreliosis spirochetes in the southeastern United States. Proc. Natl Acad. Sci. USA 100, 11642–11645 (2003).

  129. 129.

    & Lyme borreliosis in dogs and cats: background, diagnosis, treatment and prevention of infections with Borrelia burgdorferi sensu stricto. Vet. Clin. North Am. Small Anim. Pract. 40, 1103–1119 (2010).

  130. 130.

    , , , & Analysis of Borrelia burgdorferi membrane architecture by freeze-fracture electron microscopy. J. Bacteriol. 176, 21–31 (1994).

  131. 131.

    et al. Rrp1, a cyclic-di-GMP-producing response regulator, is an important regulator of Borrelia burgdorferi core cellular functions. Mol. Microbiol. 71, 1551–1573 (2009).

  132. 132.

    et al. A differential role for BB0365 in the persistence of Borrelia burgdorferi in mice and ticks. J. Infect. Dis. 197, 148–155 (2008).

  133. 133.

    et al. Borrelia burgdorferi basic membrane proteins A and B participate in the genesis of Lyme arthritis. J. Exp. Med. 205, 133–141 (2008).

  134. 134.

    et al. Borrelia burgdorferi bb0728 encodes a coenzyme A disulphide reductase whose function suggests a role in intracellular redox and the oxidative stress response. Mol. Microbiol. 59, 475–486 (2006).

  135. 135.

    et al. The coenzyme A disulfide reductase of Borrelia burgdorferi is important for rapid growth throughout the enzootic cycle and essential for infection of the mammalian host. Mol. Microbiol. 82, 679–697 (2011).

  136. 136.

    et al. Identification and molecular characterization of a cyclic-di-GMP effector protein, PlzA (BB0733): additional evidence for the existence of a functional cyclic-di-GMP regulatory network in the Lyme disease spirochete, Borrelia burgdorferi. FEMS Immunol. Med. Microbiol. 58, 285–294 (2010).

  137. 137.

    et al. Analysis of the Borrelia burgdorferi cyclic-di-GMP-binding protein PlzA reveals a role in motility and virulence. Infect. Immun. 79, 1815–1825 (2011).

  138. 138.

    , , & HrpA, a DEAH-box RNA helicase, is involved in global gene regulation in the Lyme disease spirochete. PLoS ONE 6, e22168 (2011).

  139. 139.

    , , , & Telomere resolution in the Lyme disease spirochete. EMBO J. 20, 3229–3237 (2001). An extraordinary demonstration that cp26-encoded ResT is required for telomere resolution during replication of the borrelial linear chromosome and plasmids.

  140. 140.

    et al. GuaA and GuaB are essential for Borrelia burgdorferi survival in the tick-mouse infection cycle. J. Bacteriol. 191, 6231–6241 (2009).

  141. 141.

    , , , & Analysis of the OspE determinants involved in binding of factor H and OspE-targeting antibodies elicited during Borrelia burgdorferi infection in mice. Infect. Immun. 71, 3587–3596 (2003).

  142. 142.

    et al. Immune evasion of Borrelia burgdorferi: mapping of a complement-inhibitor factor H-binding site of BbCRASP-3, a novel member of the Erp protein family. Eur. J. Immunol. 33, 697–707 (2003).

  143. 143.

    , & BBE02 disruption mutants of Borrelia burgdorferi B31 have a highly transformable, infectious phenotype. Infect. Immun. 72, 7147–7154 (2004).

  144. 144.

    et al. A plasmid-encoded nicotinamidase (PncA) is essential for infectivity of Borrelia burgdorferi in a mammalian host. Mol. Microbiol. 48, 753–764 (2003).

  145. 145.

    et al. Functional characterization of BbCRASP-2, a distinct outer membrane protein of Borrelia burgdorferi that binds host complement regulators factor H and FHL-1. Mol Microbiol. 61, 1220–1236 (2006).

  146. 146.

    et al. The critical role of the linear plasmid lp36 in the infectious cycle of Borrelia burgdorferi. Mol. Microbiol. 64, 1358–1374 (2007).

  147. 147.

    , & Fibronectin binding protein BBK32 of the Lyme disease spirochete promotes bacterial attachment to glycosaminoglycans. Infect. Immun. 74, 435–441 (2006).

  148. 148.

    , & Assessment of decorin-binding protein A to the infectivity of Borrelia burgdorferi in the murine models of needle and tick infection. BMC Microbiol. 8, 82 (2008).

  149. 149.

    et al. Resistance to Lyme disease in decorin-deficient mice. J. Clin. Invest. 107, 845–852 (2001).

  150. 150.

    , , & Both decorin-binding proteins A and B are critical for the overall virulence of Borrelia burgdorferi. Infect. Immun. 76, 1239–1246 (2008).

  151. 151.

    , , & BBA52 facilitates Borrelia burgdorferi transmission from feeding ticks to murine hosts. J. Infect. Dis. 201, 1084–1095 (2010).

  152. 152.

    et al. Borrelia burgdorferi small lipoprotein Lp6.6 is a member of multiple protein complexes in the outer membrane and facilitates pathogen transmission from ticks to mice. Mol. Microbiol. 74, 112–125 (2009).

  153. 153.

    et al. The bba64 gene of Borrelia burgdorferi, the Lyme disease agent, is critical for mammalian infection via tick bite transmission. Proc. Natl Acad. Sci. USA 107, 7515–7520 (2010).

  154. 154.

    et al. Coordinated expression of Borrelia burgdorferi complement regulator-acquiring surface proteins during the Lyme disease spirochete's mammal-tick infection cycle. Infect. Immun. 75, 4227–4236 (2007).

  155. 155.

    et al. Evidence that the BBA68 protein (BbCRASP-1) of the Lyme disease spirochetes does not contribute to factor H-mediated immune evasion in humans and other animals. Infect. Immun. 74, 3030–3034 (2006).

Download references

Acknowledgements

The authors gratefully acknowledge support from the US National Institutes of Health, National Institute for Allergy and Infectious Diseases (grants AI029735 and AI029735-20S1 to J.D.R. and M.J.C.; AI085248 to M.J.C.; AI044254 to B.S.; and AI071107, AI068799, AI082436 and AI080646 to L.T.H.). The authors also thank S. Dunham-Ems, T. Petnicki-Ocwieja, E. Troy and C. Brissette for invaluable assistance with the figures and the table, many insightful comments and careful proofreading.

Author information

Affiliations

  1. Department of Medicine and Department of Pediatrics, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.

    • Justin D. Radolf
    •  & Melissa J. Caimano
  2. Department of Genetics and Developmental Biology and Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.

    • Justin D. Radolf
  3. Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA.

    • Brian Stevenson
  4. Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts 02067, USA.

    • Linden T. Hu

Authors

  1. Search for Justin D. Radolf in:

  2. Search for Melissa J. Caimano in:

  3. Search for Brian Stevenson in:

  4. Search for Linden T. Hu in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Justin D. Radolf.

Glossary

Oligoarthritis

Arthritis affecting more than one joint in an asymmetrical pattern.

Pathognomonic

Characteristic for a particular disease.

Spirochaete

A member of the ancient and deeply branching bacterial phylum Spirochaetes, which consists of bacteria that possess a helically coiled (spiral-shaped) or wave-like morphology and a distinctive mode of motility that enables them to penetrate viscous media and tissues.

Genospecies

A term often used to describe different species of Lyme disease spirochaetes that tend to occur in particular geographic regions of the Northern Hemisphere.

Transovarial

Passed from a female adult to the larva via the egg (as occurs with spirochaetes that cause relapsing fever but not those that cause Lyme disease).

Reservoir

In the context of Lyme disease, a vertebrate species that can be persistently and asymptomatically infected with spirochaetes and, therefore, can serve as a source of infection for naive feeding ticks, usually larvae.

Trans-stadial

Transmitted to successive developmental stages of the tick.

Enzootic

Existing in nature in animal reservoirs.

Carditis

Inflammation of the heart; Lyme carditis is caused by spirochaete infection of the heart.

Spirochaetaemia

Dissemination of spirochaetes through the bloodstream.

Lipoprotein

A protein containing covalently bound fatty acids that, in bacteria, are typically at the amino terminus.

Auxotroph

An organism that is unable to synthesize an essential nutrient.

Dps

An oligomeric, ferritin-like protein that protects DNA against damage meditated by oxidative stress and starvation.

TolC

A trimeric protein that forms outer-membrane channels and associates with inner-membrane pumps to export toxic molecules from the cell.

Two-component system

A system for environmental sensing in bacteria, typically consisting of a sensor histidine kinase and a response regulator.

Fur

(Ferric uptake regulation). A metal-dependent DNA-binding protein that binds Fe2+ and regulates iron transport and related metabolic processes.

PerR

(Peroxide-sensitive repressor). A dimeric metalloprotein related to Fur. PerR orthologues contain two metal-binding sites per monomer: one site binds Zn2+, and the other binds a regulatory metal, typically Fe2+ or Mn2+.

Hypostome

A barbed protuberance of the mouthparts that anchors the tick during the blood meal.

Complement factor H and complement factor H-like protein 1

Serum proteins that prevent inadvertent activation of the alternative complement pathway. Binding of these proteins by BbCRASPs (complement regulator-acquiring surface proteins) on the surface of Lyme disease spirochaetes protects the bacteria against the lytic activity of complement generated via the alternative pathway.

Basement membrane

A collagenous matrix that encloses the surface of the tick midgut facing the haemocoel.

Haemocoel

The fluid-filled space that surrounds the tick midgut and contains the salivary glands.

Plasminogen

The inactive form of a proteolytic enzyme (zymogen) that, on activation by urokinase, degrades many proteins in the blood, including fibrin.

Pattern recognition receptors

Invariant (that is, germ-line encoded) components of the innate immune system that recognize exogenous molecules (typically of bacterial or viral origin).

Phagosomal

Within the intracellular membrane-bound compartment created when an exogenous particle is internalized by phagocytosis.

Inflammasome

A macromolecular inflammatory signalling complex in macrophages; created when pattern recognition receptors within the macrophage cytosol are activated by foreign substances or molecules (often of bacterial or viral origin).

Urokinase

A serine protease that activates plasmin, triggering a proteolytic cascade involved in thrombolysis or degradation of the extracellular matrix. Also called urokinase-type plasminogen activator.

Matrix metalloproteinases

Zinc-dependent endopeptidases that are capable of degrading extracellular matrix.

Decorin

A proteoglycan component of connective tissue; decorin binds to type I collagen fibrils in extracellular matrix.

Invariant natural killer T cells

A heterogeneous group of CD1d-restricted T cells that recognize self and foreign lipids and glycolipids. These cells constitute approximately 0.2% of peripheral blood T cells.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrmicro2714

Further reading