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Microbiology of Lyme disease

Microbiology of Lyme disease
Author:
Alan G Barbour, MD
Section Editor:
Allen C Steere, MD
Deputy Editor:
Jennifer Mitty, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: Feb 26, 2021.

INTRODUCTION — Lyme disease is the most common tick-borne disease in the United States, Canada, and Europe [1-3]. It is a bacterial infection caused by six species in the spirochete family Borreliaceae. The taxonomy of these spirochetes is undergoing revision, and the genus name may be represented as either Borrelia or Borreliella. In either case, the abbreviation for the genus is "B" and stands for both terminologies in the discussion below.

In North America, infection is caused primarily by B. burgdorferi and, less commonly, by B. mayonii in the North-Central United States. In Europe and Asia, infection is caused primarily by either B. afzelii or B. garinii, less commonly by B. burgdorferi, and uncommonly by B. spielmanii or B. bavariensis.

In nature, the reservoirs for these organisms are small mammals and birds, not deer. Humans acquire the infection from the bite of an infected tick of the genus Ixodes. The infection begins in the skin at the site of the tick bite. From there, the spirochetes may disseminate in the blood to other tissues and organs. The usual manifestations of Lyme disease involve the skin, joints, heart, and nervous system.

The microbiology of Lyme disease will be reviewed here. Topics related to immunopathogenesis, epidemiology, prevention, clinical manifestations, diagnosis, and therapy of Lyme disease are discussed separately.

●(See "Epidemiology of Lyme disease".)

●(See "Immunopathogenesis of Lyme disease".)

●(See "Prevention of Lyme disease".)

●(See "Evaluation of a tick bite for possible Lyme disease".)

●(See "Clinical manifestations of Lyme disease in adults".)

●(See "Lyme disease: Clinical manifestations in children".)

●(See "Diagnosis of Lyme disease".)

●(See "Treatment of Lyme disease".)

CHARACTERISTICS OF SPIROCHETES THAT CAUSE LYME DISEASE

Classification and genome — The spirochetes that cause Lyme disease are motile, spiral bacteria that are only distantly related to gram-negative and gram-positive pathogens. Spirochetes have two cellular membranes like gram-negative bacteria, but their flagella, the organelles of motility, are uniquely located between the inner and outer membrane, rather than on the surface. B. burgdorferi is 8 to 30 microns in length and about 0.2 microns in width. Their narrowness accounts for the inability to see unstained or Gram-stained spirochetes by standard light microscopy. (See 'Culture and staining' below.)

The genomes of B. burgdorferi and the other five species of Lyme disease agents comprise small linear chromosomes of approximately 1000 kb, and up to 21 linear and circular plasmids totaling another 400 to 500 kb [4-6]. The genes of the chromosomes are more similar between species and strains than those of the more divergent plasmids. These spirochetes were originally classified as members of the genus Borrelia. A new genus name, Borreliella ("borrelia-like"), has been proposed to distinguish the spirochetes that cause Lyme disease from those that cause relapsing fever (which retain the genus Borrelia affiliation) [7,8]. (See "Microbiology, pathogenesis, and epidemiology of relapsing fever".)

The genus name Borreliella also replaces the less formal designation of "Borrelia burgdorferi sensu lato," which refers to a cluster of species that are closely related to B. burgdorferi. Several species classified under the "sensu lato" name are not associated with any human disease. B. burgdorferi itself has commonly been distinguished in the literature from other "sensu lato" species by appending "sensu stricto," as in "B. burgdorferi sensu stricto."

Although this new classification scheme has been formally accepted for the taxonomy of Lyme disease agents and closely related species, it remains to be seen if this new genus name achieves wide usage. The medical term "borreliosis" still applies in either case.

Borrelia antigens — Some B. burgdorferi antigens that are encoded by genes on the chromosome are important for diagnostic tests (eg, Western blots). These include flagellin (the major structural protein of flagella, with an apparent size by electrophoresis of 41 kDa), certain heat shock proteins (eg, a 60 kDa protein), an inner membrane protein of 39 kDa, an integral outer membrane protein of 66 kDa, and proteins with apparent sizes 58 kDa and 93 kDa of unknown function. (See "Diagnosis of Lyme disease", section on 'Serologic tests'.)

In addition, a unique feature of B. burgdorferi and other Lyme disease species is the large number of surface-exposed lipoproteins, which are anchored in the outer membrane by covalently linked fatty acids at their N-terminal ends [4]. Plasmid-encoded antigens include the outer surface proteins OspA (31 kDa), OspB (34 kDa) [9], OspC (23 kDa) [10], the decorin-binding proteins DbpA and DbpB (18 kDa) [11], and the antigenically variable VlsE protein (35 kDa) [12]. The spirochete up- or down-regulates expression of some of these proteins at different times in its life cycle, presumably to suit each environment [13] and because of pressure from the immune response of the mammalian host [14-16].

Not all of the proteins are expressed in cultured organisms. For example, VlsE, a major immunogen, is poorly expressed in culture. Therefore, VlsE is produced as a recombinant protein in Escherichia coli for its use for immunodiagnostic assays.

Culture and staining — Direct detection of the organism can be difficult and is of limited value for diagnosis [17]. (See "Diagnosis of Lyme disease".)

●Culture – Few clinical or public health laboratories perform cultures for B. burgdorferi and related species. Given their small genomes, B. burgdorferi and the other species have limited biosynthetic capabilities and require a complex medium for growth under microaerophilic conditions in vitro. Spirochetes have been isolated from skin, blood, and cerebrospinal fluid, as well as from ticks and various animals, in Barbour-Stoenner-Kelly medium or related formulations that contain multiple nutrients as well as bovine serum albumin and rabbit serum. However, under the best of circumstances, growth is slow, with generation times of six hours or longer.

●Staining – The spirochetes can be visualized with silver stains or by immunofluorescence in biopsies of affected skin, although the numbers of bacteria are low. Unlike B. burgdorferi, B. mayonii appears to reach higher numbers in the blood of humans, and therefore it may also be detected in Wright- or Giemsa-stained smears of blood taken during acute infection [18]. (See 'Diversity of Lyme Disease species' below.)

The most commonly performed direct detection assay is polymerase chain reaction (PCR), but the paucity of organisms in tissues and the disappearance of the organism from the blood within two to four weeks of infection onset limit its utility. A more detailed discussion of PCR testing is found elsewhere. (See "Diagnosis of Lyme disease", section on 'Polymerase chain reaction'.)

PATHOGENESIS — Borrelia species do not produce potent toxins, but cause infection by migrating through tissues, disseminating in the blood, adhering to host cells, and evading immune clearance. There are no data showing that B. burgdorferi has a prolonged intracellular phase in vivo or an intracellular phase that is not treatable by antibiotics.

Under adverse conditions, spherical forms of the spirochetes may be observed. The outer membranes of the spirochetes may become detached from underlying cellular structures, but these so-called "cyst"-like forms do not represent a different stage in the life cycle of the spirochetes. There is no proven clinical significance for these "cyst"-like forms.

Ecologic niche — Borrelia species are obligate parasites; there are no known free-living forms. The spirochetes cycle between two different environments: the tick (a poikilothermic invertebrate without an adaptive immune system), and mammals and birds (homeothermic vertebrates with well-developed adaptive immune systems). They are transmitted primarily by ticks, or very rarely by direct contact with fresh infected blood or tissues, but not by respiratory secretions, urine, feces, or fomites. (See "Epidemiology of Lyme disease".)

Borrelia species are microaerophilic and grow optimally in carbon dioxide concentrations typical of the internal milieu of mammals and birds. These bacteria are killed by exposure to temperatures over 50°C for more than a few minutes, hypotonic or hypertonic environments, drying, common disinfectants (eg, bleach), and detergents. They do not form spores. (See "Prevention of Lyme disease".)

In comparison with genomes of free-living bacteria, the small Borrelia genome encodes few proteins with biosynthetic activity. Thus, Borrelia species depend upon the animal host or a rich culture medium in the laboratory for most nutritional requirements. (See 'Culture and staining' above.)

Protein expression — B. burgdorferi expresses different repertoires of proteins to suit each environment [19,20]. To transit from the tick midgut (where the B. burgdorferi are located prior to initiation of feeding) to the tick salivary gland, the organism rapidly down-regulates outer surface protein (Osp) A and upregulates OspC. Down-regulation of OspA facilitates detachment from the tick midgut and transit to the salivary glands [21,22]. Upregulation of OspC facilitates invasion of bacteria into skin [23-25]. Additional discussions of outer surface proteins are found elsewhere. (See 'Borrelia antigens' above and "Immunopathogenesis of Lyme disease", section on 'Outer surface protein variations'.)

Although Borrelia species do not produce lipid A-containing endotoxin [26], they do produce lipoproteins that are ligands for toll-like receptors on mononuclear blood cells and other cells [27]. Binding to these receptors can lead to release of pro-inflammatory cytokines with effects qualitatively similar to responses to endotoxin. A Jarisch-Herxheimer reaction may appear in some patients with Lyme soon after the start of antibiotic treatment. (See "Immunopathogenesis of Lyme disease", section on 'Toll-like receptors'.)

Immune response — Some surface-exposed lipoproteins, such as the strain-specific OspC protein, appear to be T-cell independent antigens in hosts. This would explain the antibody responses to OspC during early infection that are limited to IgM and short-lived [28]. Because B. burgdorferi do not secrete toxins, proteases, or other destructive molecules, the majority of the symptoms seen with human Lyme disease are due to the combined effects of the host innate and adaptive immune responses and lytic release of inflammatory bacterial components that follow. This is discussed in detail separately. (See "Immunopathogenesis of Lyme disease".)

DIVERSITY OF LYME DISEASE SPECIES

Overview — Three species account for most cases of Lyme disease in the world:

●B. burgdorferi causes Lyme disease in North America and less extensively in Europe.

●B. afzelii and B. garinii are the predominant species in Europe and Asia.

Different species of Ixodes ticks serve as vectors in different regions. This is discussed in detail separately. (See "Epidemiology of Lyme disease", section on 'Regional distribution'.)

Several more distantly related spirochetes are the agents of tick- and louse-borne relapsing fever, most clinical manifestations of which have little in common with Lyme disease. However, there is sufficient sequence similarity for some proteinaceous antigens of the Lyme disease group of species and the relapsing fever group of species for there to be antigenic cross-reactivity in immunoassays. Included in this group of relapsing fever agents is Borrelia miyamotoi, which is transmitted by the same species of Ixodes ticks that transmit Lyme disease in North America and Eurasia [29]. These agents are discussed in greater detail elsewhere. (See "Microbiology, pathogenesis, and epidemiology of relapsing fever" and "Clinical features, diagnosis, and management of relapsing fever" and "Borrelia miyamotoi infection".)

Geographic distribution

North America — In Northeastern and North-Central United States and bordering regions of Canada, B. burgdorferi is the principal cause of Lyme disease in humans [30]. The organism is transmitted by I. scapularis ticks.

In northern California, and some other coastal and foothill regions of far-western North America, human cases of Lyme disease are associated with exposure to B. burgdorferi-infected Ixodes pacificus ticks. I. pacificus are infected with B. burgdorferi, but at a 10-fold lower frequency than occurs in the northeastern United States [31].

The only other species that has been established as a cause of Lyme disease in North America is B. mayonii, which is also transmitted by I. scapularis ticks in north-central United States [32]. B. mayonii has not been observed in I. pacificus ticks. B. mayonii has been distinguished from B. burgdorferi by its ability to achieve higher concentrations in the blood in some patients. (See 'Culture and staining' above.)

Other related species in the United States that have life cycles in nature involving Ixodes ticks include B. americana, B. andersoni, B. bissettii, B. carolinensis, and B. kurtenbachii [1]. However, to date, none of these species have been established as causes of human disease (ie, they have not been isolated in culture from patients). The usual vectors of most of these other types of spirochetes are Ixodes species of ticks that humans would seldom encounter or be bitten by.

Europe and Asia — In Europe and Asia, the diversity of Lyme disease spirochetes causing human disease is greater than in North America. (See "Epidemiology of Lyme disease", section on 'Regional distribution'.)

●In Europe, B. afzelii and B. garinii commonly infect humans [33,34]. B. burgdorferi is a considerably less common cause in Europe and has not yet been found in Asia. Strains of B. burgdorferi in Europe and North America are unique to each continent [35].

●In Asia, B. afzelii and B. garinii are also thought to be the most common causes of Lyme disease. Unlike North America and western Europe, where most infections are acquired from the bite of a nymphal tick, in Asia and Asian Russia, transmission to humans is mainly by the adult stage of the tick [36].

●B. bavariensis is closely related to B. garinii [37]. While B. bavariensis is distributed across the Eurasian continent, the infrequent cases of human disease have only been reported from Europe.

●B. spielmanii has been implicated in human disease in Europe, but in a survey from Germany, this species occurred less frequently in ticks than B. garinii, B. afzelii, or B. burgdorferi [38].

There are differences in the ecology of the species, especially between the two most prevalent species, B. afzelii and B. garinii. B. afzelii is mainly associated with rodents as reservoirs, whereas B. garinii is mainly associated with birds [1,39]. This pattern of reservoir hosts for these spirochetes is attributed wholly, or in part, to the relative susceptibility of specific host complement lysis. (See 'Ecologic niche' above and "Immunopathogenesis of Lyme disease", section on 'Evasion of complement-mediated killing'.)

In South America, B. chilensis was isolated from Ixodes ticks of that continent [40]. However, the risk of this organism to humans has not been established.

Relationship to clinical manifestations

Differences among species — Biologic differences have been observed among the three predominant species of Lyme disease agents. In an in vitro study that included representatives of the three species, B. burgdorferi stimulated macrophages to secrete higher levels of cytokines and chemokines than did B. afzelii or B. garinii [41]. (See "Immunopathogenesis of Lyme disease".)

These biologic differences are likely to account for some of the differences in clinical manifestations in patients in Europe compared with North America. As an example, although all three species have been recovered from various sites in patients (eg, skin, blood, and cerebrospinal fluid), infection with B. afzelii is associated with a lower risk of neurologic disease than infection with either B. garinii or B. burgdorferi [42]. In addition, B. burgdorferi strains from Europe and the United States differ genetically, and the clinical disease caused by B. burgdorferi in Europe is more like that associated with B. afzelii and B. garinii, rather than B. burgdorferi in the United States [43]. More detailed discussions of the clinical differences between Lyme disease in Europe and the United States are presented elsewhere. (See "Clinical manifestations of Lyme disease in adults", section on 'United States versus Europe'.)

Differences among strains — In Lyme disease-endemic regions of North America, there are usually 10 to 15 genetically distinct strains of B. burgdorferi circulating among wildlife and ticks in a given area [30,31]. Strain typing by DNA sequence (genotyping) has been by outer surface protein C gene, a set of conserved chromosomal genes, and the spacer sequence between the 16S and 23S ribosomal RNA genes. The last typing scheme has been abbreviated "RST," and there are three major RST types: 1, 2, and 3. However, these methods are being supplanted by whole-genome sequencing.

The different strains can impact:

●Immunity from infection – Immunity from infection is largely strain-specific, and infection with one strain generally does not confer protection against another strain. However, it seems that immunity may develop across strains within the same geographic region. As an example, reinfection has not been observed in patients with Lyme arthritis who typically have expanded antibody responses to many spirochetal proteins that persist for years [44].

●Risk of dissemination – Some strains of B. burgdorferi are associated with a higher frequency of disseminated infection in humans and other mammals compared with others [45-51]. Moreover, RST1 strains have been associated with more severe early disease [52] and more frequent antibiotic-refractory Lyme arthritis [52,53]. However, the basis for these strain differences is not known. Whether identification of the strain of an infection will lead to more effective management of the patient (eg, a longer course of antibiotics for some strains) has not been evaluated.

●Inflammatory potential – Strains of B. burgdorferi from the United States and Europe were found to differ in their inflammatory potential. In general, United States strains generally elicit higher levels of cytokines and chemokines associated with innate and Th1-adaptive immune responses than strains from Europe [43].

There are some strains of B. burgdorferi in the United States that occur in all three regions where the microbe is endemic: the Northeast, North-Central, and Far West. One of these is strain B31, which was the first laboratory isolate of this pathogen, and one of the most common. Other strains have more limited distributions (eg, occurring in the Midwest but not in the Northeast or the Far West) [54]. A similar situation characterizes populations of B. afzelii and B. garinii in Europe [35].

The mix of strains in a given area is probably determined in part by the adaptive immune responses, including strain-specific antibodies, of host animals over time. There may also be strain differences in host associations, such as different patterns of susceptibility to complement of various vertebrate species [39]. Susceptibility of B. burgdorferi to the nonimmune, bactericidal effects of the serum of lizards is one of the explanations for the lower prevalence of B. burgdorferi in Ixodes ticks in the far-western and southeastern United States. Although lizards are common hosts for I. pacificus and I. scapularis ticks in these respective regions [55], when an infected tick feeds on a lizard, the blood meal has a sterilizing action. (See "Immunopathogenesis of Lyme disease".)

SUMMARY

●Lyme disease is the most common tick-borne disease in the United States, Canada, and Europe. It is a bacterial infection caused by six species in the spirochete family Borreliaceae. The taxonomy of these spirochetes is undergoing revision, and the genus name may be represented as either Borrelia or Borreliella. (See 'Introduction' above.)

●Lyme disease spirochetes are motile, spiral bacteria that are only distantly related to gram-negative and gram-positive pathogens. Their genomes comprise small linear chromosomes and linear and circular plasmids. (See 'Classification and genome' above.)

●Direct detection of the organism can be difficult. Given their small genome, B. burgdorferi and the other species have limited biosynthetic capabilities and require a complex medium and microaerophilic conditions for growth in vitro. Under the best of circumstances, growth is slow. The spirochetes can be visualized with silver stains or by immunofluorescence in biopsies of affected skin; however, the numbers of bacteria are low. (See 'Culture and staining' above.)

●B. burgdorferi and related species do not produce toxins, but cause infection by migrating through tissues, adhering to host cells, and evading immune clearance. (See 'Pathogenesis' above.)

●In North America, infection is caused primarily by B. burgdorferi. In Europe and Asia, B. burgdorferi is less common, and infection is caused primarily by either B afzelii or B. garinii. (See 'Geographic distribution' above.)

●Biologic differences have been observed between different species of Lyme disease agents and among strains within a given species. These are likely to account for some of the differences in clinical manifestations in patients in Europe compared with North America. (See 'Relationship to clinical manifestations' above.)

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  52. Strle K, Shin JJ, Glickstein LJ, Steere AC. Association of a Toll-like receptor 1 polymorphism with heightened Th1 inflammatory responses and antibiotic-refractory Lyme arthritis. Arthritis Rheum 2012; 64:1497.
  53. Jones KL, McHugh GA, Glickstein LJ, Steere AC. Analysis of Borrelia burgdorferi genotypes in patients with Lyme arthritis: High frequency of ribosomal RNA intergenic spacer type 1 strains in antibiotic-refractory arthritis. Arthritis Rheum 2009; 60:2174.
  54. Barbour AG, Travinsky B. Evolution and distribution of the ospC Gene, a transferable serotype determinant of Borrelia burgdorferi. MBio 2010; 1.
  55. Lane RS, Quistad GB. Borreliacidal factor in the blood of the western fence lizard (Sceloporus occidentalis). J Parasitol 1998; 84:29.
Topic 16138 Version 17.0

References

1 : The expanding Lyme Borrelia complex--clinical significance of genomic species?

2 : Lyme disease.

3 : Lyme borreliosis.

4 : Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi.

5 : Megabase-sized linear DNA in the bacterium Borrelia burgdorferi, the Lyme disease agent.

6 : A bacterial genome in flux: the twelve linear and nine circular extrachromosomal DNAs in an infectious isolate of the Lyme disease spirochete Borrelia burgdorferi.

7 : A phylogenomic and molecular marker based proposal for the division of the genus Borrelia into two genera: the emended genus Borrelia containing only the members of the relapsing fever Borrelia, and the genus Borreliella gen. nov. containing the members of the Lyme disease Borrelia (Borrelia burgdorferi sensu lato complex).

8 : Division of the genus Borrelia into two genera (corresponding to Lyme disease and relapsing fever groups) reflects their genetic and phenotypic distinctiveness and will lead to a better understanding of these two groups of microbes (Margos et al. (2016) There is inadequate evidence to support the division of the genus Borrelia. Int. J. Syst. Evol. Microbiol. doi: 10.1099/ijsem.0.001717).

9 : Molecular analysis of linear plasmid-encoded major surface proteins, OspA and OspB, of the Lyme disease spirochaete Borrelia burgdorferi.

10 : Use of recombinant OspC from Borrelia burgdorferi for serodiagnosis of early Lyme disease.

11 : Adherence of Borrelia burgdorferi to the proteoglycan decorin.

12 : Antigenic variation in Lyme disease borreliae by promiscuous recombination of VMP-like sequence cassettes.

13 : Induction of an outer surface protein on Borrelia burgdorferi during tick feeding.

14 : Tick-specific borrelial antigens appear to be upregulated in American but not European patients with Lyme arthritis, a late manifestation of Lyme borreliosis.

15 : Outer surface protein A protects Lyme disease spirochetes from acquired host immunity in the tick vector.

16 : Identification of an ospC operator critical for immune evasion of Borrelia burgdorferi.

17 : Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease.

18 : Identification of a novel pathogenic Borrelia species causing Lyme borreliosis with unusually high spirochaetaemia: a descriptive study.

19 : Regulation of expression of major outer surface proteins in Borrelia burgdorferi.

20 : Arthropod- and host-specific gene expression by Borrelia burgdorferi.

21 : TROSPA, an Ixodes scapularis receptor for Borrelia burgdorferi.

22 : OspC facilitates Borrelia burgdorferi invasion of Ixodes scapularis salivary glands.

23 : OspC-independent infection and dissemination by host-adapted Borrelia burgdorferi.

24 : Borrelia burgdorferi OspC protein required exclusively in a crucial early stage of mammalian infection.

25 : Outer-surface protein C of the Lyme disease spirochete: a protein induced in ticks for infection of mammals.

26 : Absence of lipopolysaccharide in the Lyme disease spirochete, Borrelia burgdorferi.

27 : Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2.

28 : Humoral immune response to outer surface protein C of Borrelia burgdorferi in Lyme disease: role of the immunoglobulin M response in the serodiagnosis of early infection.

29 : Niche partitioning of Borrelia burgdorferi and Borrelia miyamotoi in the same tick vector and mammalian reservoir species.

30 : Phylogeography of Borrelia burgdorferi in the eastern United States reflects multiple independent Lyme disease emergence events.

31 : Population structure of the lyme borreliosis spirochete Borrelia burgdorferi in the western black-legged tick (Ixodes pacificus) in Northern California.

32 : Borrelia mayonii sp. nov., a member of the Borrelia burgdorferi sensu lato complex, detected in patients and ticks in the upper midwestern United States.

33 : Delineation of Borrelia burgdorferi sensu stricto, Borrelia garinii sp. nov., and group VS461 associated with Lyme borreliosis.

34 : Borrelia burgdorferi sensu lato diversity and its influence on pathogenicity in humans.

35 : Sequence typing reveals extensive strain diversity of the Lyme borreliosis agents Borrelia burgdorferi in North America and Borrelia afzelii in Europe.

36 : Comparative ecology and epidemiology of lyme disease and tick-borne encephalitis in the former Soviet Union.

37 : Borrelia bavariensis sp. nov. is widely distributed in Europe and Asia.

38 : Epidemiological aspects and molecular characterization of Borrelia burgdorferi s.l. from southern Germany with special respect to the new species Borrelia spielmanii sp. nov.

39 : Host association of Borrelia burgdorferi sensu lato--the key role of host complement.

40 : Borrelia chilensis, a new member of the Borrelia burgdorferi sensu lato complex that extends the range of this genospecies in the Southern Hemisphere.

41 : Borrelia burgdorferi stimulates macrophages to secrete higher levels of cytokines and chemokines than Borrelia afzelii or Borrelia garinii.

42 : The emergence of Lyme disease.

43 : Differences in Genotype, Clinical Features, and Inflammatory Potential of Borrelia burgdorferi sensu stricto Strains from Europe and the United States.

44 : Persistence of immunoglobulin M or immunoglobulin G antibody responses to Borrelia burgdorferi 10-20 years after active Lyme disease.

45 : Borrelia burgdorferi genotype predicts the capacity for hematogenous dissemination during early Lyme disease.

46 : Borrelia burgdorferi genetic markers and disseminated disease in patients with early Lyme disease.

47 : Four clones of Borrelia burgdorferi sensu stricto cause invasive infection in humans.

48 : Genetic diversity of Borrelia burgdorferi in lyme disease patients as determined by culture versus direct PCR with clinical specimens.

49 : Disease severity in a murine model of lyme borreliosis is associated with the genotype of the infecting Borrelia burgdorferi sensu stricto strain.

50 : Fitness variation of Borrelia burgdorferi sensu stricto strains in mice.

51 : Outer surface protein polymorphisms linked to host-spirochete association in Lyme borreliae.

52 : Association of a Toll-like receptor 1 polymorphism with heightened Th1 inflammatory responses and antibiotic-refractory Lyme arthritis.

53 : Analysis of Borrelia burgdorferi genotypes in patients with Lyme arthritis: High frequency of ribosomal RNA intergenic spacer type 1 strains in antibiotic-refractory arthritis.

54 : Evolution and distribution of the ospC Gene, a transferable serotype determinant of Borrelia burgdorferi.

55 : Borreliacidal factor in the blood of the western fence lizard (Sceloporus occidentalis).