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Borrelia burgdorferi
Lyme disease spirochete

Taxonomy

Taxonomic lineage

cellular organisms - Bacteria - Spirochaetes - Spirochaetes (class) - Spirochaetales - Spirochaetaceae - Borrelia - Borrelia burgdorferi group - Borrelia burgdorferi

Phylum Spirochaetes

Spirochaetes is unique phylum of bacteria: in addition to a typical bacterial plasma membrane surrounded by a cell wall containing peptidoglycan, they have an outer lipid bilayer membrane, also referred to as an outer membrane sheath. The space between the protoplasmic cell cylinder and the outer membrane sheath is called periplasm, or periplasmic space. Flagella of spirochetes are similar to the flagella of rod-shaped bacteria but are located between the protoplasmic cell cylinder and outer membrane sheath and are referred as periplasmic flagella (PF). Each PF is attached to one end of the cell cylinder and extends toward the opposite end. These flagella unable spirochetes to swim faster in a high-viscosity gel-like medium than in low-viscosity media. For most of the bacteria the situation is reverse. The phylum contains the only class Spirochaetes with single order Spirochaetales. The order includes several important human pathogens such as Leptospira (family Leptospiraceae), Borrelia and Treponema (family Spirochaetaceae).
Treponema pallidum, causative agent of syphilis: taxonomy, history, biology at MetaPathogen

Genus Borrelia

Genus Borrelia was named after French bacteriologist Amedée Borrel (1867–1936) in 1907is. These organisms cause tick-borne and louse-borne relapsing fever in humans and animals. For example, B. hermsii, transmitted by Ornithodoros hermsi ticks, causes relapsing fever in the Western United States, and B. recurrentis causes louse-borne relapsing fever worldwide. B. burgdorferi was isolated from patients with arthritis-like symptoms by Willy Burgdorfer and Alan G. Barbour in 1982, is the etiologic agent of Lyme disease.

Borrelia burgdorferi group

Borrelia burgdorferi group and Borrelia burgdorferi sensu lato are synonyms. Three species of B. burgdorferi cause most human disease: B. burgdorferi sensu stricto, B. garinii, and B. afzelii. B. burgdorferi sensu stricto is the only species associated with human disease in the United States, whereas all three species occur in Europe, and B. garinii and B. afzelii occur in Asia. B. garinii and B. afzelii are antigenically distinct from B. burgdorferi sensu stricto, and these differences may account for the variation in disease symptoms in different geographic regions.

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General information

• Morphology

  B. burgdorferi are relatively large bacteria with a diameter of 0.33 μm and a length of 10-20 μm. Wild-type cells at rest have a flat-wave morphology having mostly planar, sinusoidal deformations. A swimming cell usually rotates counterclockwise in cork-screw manner as waves propagate along its length. Attached to each end are 7-11 periplasmic flagella that overlap in the center of the cell. The flagella influence cell shape: with them, the cells are wave-like, and without them, they are rod-shaped. The flagella-produced specific spirochetal motility and together with ability of the bacterium to hijack some host's enzymes such as plasminogen enable it to quickly disseminate throughout the host's body even in poorly vascularized connective tissues without using blood vessels. Another potential advantage to the flagellar arrangement of spirochetes is the shielding of the highly conserved and immunogenic flagella from the host immune system.

• Geographic distribution

  There is a distinct geographic distribution of Lyme disease in both the United States and Europe. Twelve US states account for 95% of the reported cases of Lyme disease. These states include the mid-Atlantic and coastal northeastern states. The highest incidence of Lyme disease in Europe occurs in central Europe.

• Genome

  The genome of B. burgdorferi s.s. species consists of a linear chromosome including 910,725 bp and 21 extrachromosomal elements (plasmids) consisting of about 613,000 bp. Nine plasmids are circular and 12 are linear. circular and 12 linear). This abundance of plasmids (40% of total genome) is unusual and unique in bacterial world with Chlamydia coming in a distant second with 7 plasmids. Today, the genome of B. burgdorferi s.s. (B31) is completely sequenced. The linear structure of the chromosome and many of the plasmids is also unusual in the bacterial world. Other bacteria with linear chromosomes are Streptomyces coelicolor and S. avermitilis, Rhodococcus sp. strain RHA1 and Agrobacterium tumefaciens. Most genes encoded on the B. burgdorferi chromosome are commonly found in other bacterial genomes. Majority of genes on the plasmid component of the genome appears to be unique to genus Borrelia.
  

• Survival strategies

  In addition to its complex genetic makeup, B. burgdorferi engages in so-called "stealth pathology" to evade the host's immune response. Stealth pathology involves following strategies: (1) suppression of host immune system; (2) mutagenesis (possible occurrence of antibiotic resistant mutants); (3) life stage switching (dormant cysts and actively reproducing and disseminating bacteria); (4) variable antigen production; (5) physical seclusion (colonization of poorly vascularized tissues); (6) secreted factors (enable dissemination by helping bacteria to adhere to cells and pierce the cell walls).

• Gene switching depending on host

  Surface lipoproteins Osp (outer surface proteins), OspA, OspB, OspC, OspD, OspE and OspF, plays an essential role in the pathogenicity of Lyme borreliosis. The survival of B. burgdorferi in tick and in the organism of mammals is partly attributed to the selective expression of these lipoproteins: the expression of ospA and ospB is immediately activated when the spirochetes penetrate into the vector arthropod whereas during the transmission from the vector to the host-vertebrate, the expression of ospA and ospB is reduced and synthesis of OspC, DbpA and BBK32 is increased.

Life stages & transmission cycle

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Borrelia burgdorferi is transmitted to humans by Ixodes ticks. These small, dark-colored ticks have a 2-year life cycle made up of four developmental stages: egg, larva, nymph, and adult. Eggs are laid in spring and hatch into larvae during the late summer. Larvae feed on small animals (usually white-footed mouse, Peromyscus leucopus) and can acquire B. burgdorferi infection at this stage. The larvae then molt into nymphs, which feed again the following spring to early summer and may transmit the infection to the new host including humans and domestic animals. Nymph must feed for 36-48 hours in order totransmit the parasite. Nymphs molt into adult ticks in mid-October and early-November, when the adult female ticks feed again, mainly on large animals such as deer.

Small mammals and some birds, particularly the white-footed mouse, are important in the transmission cycle of B. burgdorferi, because they serve as reservoirs of the pathogen. Although deer is not reservoir-competent (B. burgdorferi does not live in its organism), they also are important in the cycle because as the principal hosts for the adult ticks they provide bloodmeal that is necessary for a female to lay eggs. Eggs are not infected.

Together with Borrelia burgdorferi, ticks can transmit such parasites as Babesia microti (babesiosis) and Anaplasma phagocytophilum (granulocytic ehrlichiosis).

Ixodes scapularis, black-legged tick, deer tick - vector of Lyme disease - life cycle, pictures at MetaPathogen

Lyme disease

• Discovery

  Lyme disease was first described in the late 1970s during an investigation of an unusual epidemic of juvenile rheumatoid arthritis in Lyme, Connecticut. Manifestations of this disease were evident in Europe from the beginning of the 20^th century. The causative agent was isolated from Ixodes ticks in 1982, marking the start of a new era in the understanding of this disease. Currently, Lyme disease is considered the most common vector-borne illness in the United States.

• Statistics

  Lyme disease ranks among the top 10 notifiable conditions in the United States. In 2009, state and territorial health departments reported 29,959 confirmed and 8,509 probable cases to the Centers for Disease Control and Prevention (CDC). Geographically, the distribution of Lyme disease cases is highly focal, with 10 states in the Northeast and upper Midwest accounting for 93% of all reported cases. In counties in which Lyme disease is highly endemic, annual incidence can exceed 250 reported cases per 100,000 population.
  As with other tick-borne diseases, the incidence of Lyme disease has a bimodal distribution with respect to age. Rates are highest among children 5–9 years of age (8.6 cases per 100,000 population) and among adults 55–59 years of age (7.8 cases per 100,000 population). The lowest rate is seen among young adults 20–24 years of age (3.0 cases per 100,000 population). Male patients account for 53% of reported cases.

• Symptoms and pathologies

  Lyme disease usually begins with the characteristic skin lesion, erythema migrans, at the site of the tick bite (~80-90% of patients). The incubation period from infection to onset of erythema migrans typically is 7 to 14 days (ranging from 1 to 30 days). Classically, erythema migrans starts as a red papule at the site of the bite, which gradually expands to a round lesion with red borders and partial central clearing. Constitutional symptoms such as arthralgia (pain in the joints), myalgia (pain in muscles), and severe fatigue are common, lymphadenopathy (enlargement of lymph nodes) also may occur.
  After several days or weeks, the spirochetes spread hematogenously, and patients may develop multiple erythema migrans lesions. Patients may develop neurologic (15% to 20% of untreated patients), cardiac (4% to 8%), and more severe rheumatologic symptoms. Borrelia lymphocytoma is a firm, painless, bluish-red nodular lesion usually localized on the earlobe or nipple. Usually it occurs in Europe and is associated with B. afzelii and B. garinii infection. These early signs may resolve even if the patient is untreated. Acrodermatitis chronica atrophicans, a chronic skin disease that occurs in Europe and Asia, is associated primarily with B. afzelii infection The reddish skin lesions usually found on the surfaces of the limbs can progress to atrophy of the skin over a period of years.

• Chronic Lyme disease

  Chronic Lyme disease is a confusing term used to describe different patient populations, including:
  1. patients with late Lyme disease;
  2. patients wit with post-Lyme disease syndrome;
  3. patients who have no evidence of Lyme disease.
  
  Post-Lyme disease syndrome occurs in a few patients with an episode of well-documented Lyme disease who continue to experience fatigue, sleep disorders, headache, memory and concentration difficulties, myalgias, and arthralgias after receiving adequate antibiotic therapy. The cause of this syndrome currently is unknown.

• Lyme disease in dogs

  Majority (95%) of exposed dogs remain clinically normal. If become ill, arthritis, fever, anorexia, lymphadenopathy are most common symptoms in dogs. Glomerulonephritis may develop. Unlike humans, erythema migrans does not occur in dogs.

• Vaccination

  A human B. burgdorferi vaccine is not currently available, but several vaccines are widely used to protect dogs from B. burgdorferi. Estimates of efficacy range from 50% to 85%. However, vaccinated dogs may still become infected because protection can be incomplete, and the protective immune response wanes over time.

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Diagnostics of Lyme disease

• Erythema migrans

  An erythema migrans (EM) rash is recognized in 80-90% of patients with early Lyme disease. Erythema migrans within 3 to 30 days of tick exposure with a 5 cm diameter is the only symptom of Lyme disease that is sufficient for diagnosis and makes further laboratory testing unnecessary.

• Serologic laboratory testing

  A major problem is that current commercial Lyme serologic tests are not sensitive enough for diagnosis, especially during the later stages of disease. The Centers for Disease Control and Prevention (CDC) advocates a "2-tier" testing system using an ELISA or immunofluorescence assay as a screening test, followed by a Western blot for confirmation if the result of the ELISA or immunofluorescence assay is positive.
  CDC testing guideline and explanation

Treatment of Lyme disease

• Many studies have shown that Lyme disease is treated successfully with antibiotics in the majority of cases, and patients with objective evidence of treatment failure are rare with currently recommended regimens. Patients with late manifestations can have a slower response to therapy, sometimes taking weeks or months to recover. Some patients may have incomplete resolution due to irreversible damage, as can occur in facial nerve palsy with residual facial weakness. A few patients may develop antibiotic-refractory Lyme arthritis, when synovitis persists for months to years after antibiotic therapy, it is most likely due to autoimmunity triggered by the infection.
• Oral therapy is recommended for early and uncomplicated infection, including isolated facial nerve palsy. Doxycycline and amoxicillin are the drugs of choice. Doxycycline is contraindicated in children younger than 8 years of age and in pregnant or lactating women. During doxycycline therapy, patients should be advised to wear sunscreen and avoid sun exposure, as the drug may cause photosensitivity. Amoxicillin is the drug of choice for children younger than 8 years of age and pregnant or lactating women. Cefuroxime axetil is a second-line alternative because of its slighter higher cost. The recommended duration of therapy varies from 14 to 28 days.
• Intravenous antibiotics generally are recommended for treating neurologic Lyme disease and for the initial therapy of patients with more severe cardiac disease. Patients with severe cardiac disease require hospitalization. The antibiotic course may be completed with oral therapy. Intravenous (IV) ceftriaxone is the most commonly used parenteral therapy, but IV cefotaxime or IV penicillin G also may be used. Patients with Lyme encephalopathy have gradual improvement in their symptoms, usually starting a few months after completion of therapy, and continue to improve slowly for up to 1 to 2 years. For patients with Lyme arthritis (with no neurologic symptoms), initial therapy usually is with oral antibiotics for 28 days. A course of oral therapy may be repeated if the patient has persistent joint swelling. Patients who do not respond may receive IV therapy for 2 to 4 weeks. For patients with antibiotic-refractory Lyme arthritis, treatment with anti-inflammatory agents is recommended.

References

• Miklossy J, Kasas S, Zurn AD, McCall S, Yu S, McGeer PL. Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis. J Neuroinflammation. 2008 Sep 25;5:40.

  

  Characteristic morphology of B. burgdorferi seen by various techniques following one week of culture in BSKII medium.
  Dark field microscopy images of strain B31 showing the usual spiral form of spirochetes: (A) and their agglomeration into colony-like masses (B).
  Similar spiral morphology of strain B31 is illustrated by OspA immunoreactivity (C) and
  by atomic force microscopy (AFM) imaging (D).
  Dark field microscopy images showing the typical spiral form (E) and colony formation (F) of Sstrain ADB1.
  Immunostaining of strain ADB1 with a polyclonal anti-B. burgdorferi antibody (Biodesign, B65302R). The green fluorescent immunoreaction was revealed with an FITC tagged secondary antibody. (G)
  Silver impregnation of strain ADB1 with the Bosma Steiner microwave technique. (H)
  
  Bars: A, C = 10 μm; B = 30 μm; D = 1 μm; E, G, H = 8 μm; F = 25 μm.

• Norris SJ. How do Lyme Borrelia Organisms Cause Disease? The Quest for Virulence Determinants. Open Neurol J. 2012; 6: 119–123.

  

  Similarities of the time course of two invasive, persistent spirochetal infections, Lyme borreliosis and syphilis.

• Aucott J, Morrison C, Munoz B, Rowe PC, Schwarzwalder A, West SK. Diagnostic challenges of early Lyme disease: lessons from a community case series. BMC Infect Dis. 2009 Jun 1;9:79.

  

  Classic bull's eye EM with initial misdiagnosis as urinary tract infection.
  A 78 year old women presented to an urgent care center with 3 days of fever, mild headache and the absence of rhinitis, cough or typical upper respiratory viral symptoms. The physical exam showed a temperature of 102 degrees Fahrenheit and a skin rash was not noted. Urinalysis showed 5–10 WBCs, a diagnosis of pylonephritis was made, and ciprofloxacin was initiated. The patient returned the following day when she noticed a large, red rash on her side. The patient was referred to one of the authors (JA) who confirmed the diagnosis of Lyme disease. Ciprofloxacin was discontinued, doxycycline initiated and the rash resolved. Serology returned with a positive ELISA and confirmatory western blot.

• Moriarty TJ, Norman MU, Colarusso P, Bankhead T, Kubes P, Chaconas G. Real-time high resolution 3D imaging of the lyme disease spirochete adhering to and escaping from the vasculature of a living host. PLoS Pathog. 2008 Jun 20;4(6):e1000090.

  

  Real-time visualization of B. burgdorferi in the microvasculature of a living murine host.
  A time-lapse microscopy series of two GFP-expressing B. burgdorferi in the capillary of the skin of a living C57 mouse is shown. The top spirochete is motile while the bottom spirochete is stationary. Time (t) in seconds (s) is shown above or below each micrograph in the series. Images were obtained by spinning disk confocal IVM after jugular vein injection of fluorescent B. burgdorferi. Endothelial cells were labeled with Alexa Fluor 555-conjugated antibody to PECAM-1, which is expressed on endothelial cells and concentrates at intercellular junctions. Direction of blood flow in this vessel is unknown. The video from which these micrographs were extracted is presented as Video S2. Video S3.

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