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


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.

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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


  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


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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Justin D. Radolf.



Arthritis affecting more than one joint in an asymmetrical pattern.


Characteristic for a particular disease.


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.


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


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).


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.


Transmitted to successive developmental stages of the tick.


Existing in nature in animal reservoirs.


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


Dissemination of spirochaetes through the bloodstream.


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


An organism that is unable to synthesize an essential nutrient.


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


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.


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


(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+.


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.


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


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).


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


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).


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.


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.

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