Microbiology of Lyme disease: Difference between revisions

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

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

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

Species and strains

Until recently, only three genospecies were thought to cause Lyme disease (borreliosis): B. burgdorferi sensu stricto (the predominant species in North America, but also present in Europe); B. afzelii; and B. garinii (both predominant in Eurasia). The complete genomes of B. burgdorferi sensu stricto strain B31, B. afzelii strain PKo and B. garinii strain PBi are known. B. burgdorferi strain B31 was derived by limited dilutional cloning from the original Lyme-disease tick isolate derived by Alan Barbour.

Emerging genospecies

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

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

B. lusitaniae ^[7] in Europe (especially Portugal), North Africa and Asia.

B. bissettii ^[8]^[9] in the U.S. and Europe.

B. spielmanii ^[10]^[11] in Europe.

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

The B. miyamotoi spirochete, related to the relapsing fever group of spirochetes, is also suspected of causing illness in Japan. Spirochetes similar to B. miyamotoi have recently been found in both Ixodes ricinus ticks in Sweden and I. scapularis ticks in the U.S.^[12]^[13]^[14]

B. lonestari

Apart from this group of closely related genospecies, additional Borrelia species of interest include B. lonestari, a spirochete recently detected in the Amblyomma americanum tick (lone star tick) in the U.S.^[15] B. lonestari is suspected of causing southern tick-associated rash illness (STARI), also known as Masters disease in honor of its discoverer, Dr. Edwin Jordan Masters. The illness follows a lone star tick bite, and clinically resembles Lyme disease, but sufferers usually test negative for Lyme.^[16] There is currently no diagnostic test available for STARI/Masters, and no official treatment protocol, though antibiotics are generally prescribed.

Epidemiology

Lyme disease is most endemic in Northern Hemisphere temperate regions.^[17]^[18] However, sporadic cases of Lyme disease have been described in other areas of the world.

The number of reported cases of the borreliosis have been increasing, as are endemic regions in North America. Of cases reported to the United States Centers for Disease Control and Prevention (CDC), the rate of Lyme disease infection is 7.9 cases for every 100,000 persons. In the ten states where Lyme disease is most common, the average was 31.6 cases for every 100,000 persons for the year 2005.^[19] Although Lyme disease has now been reported in 49 of 50 states in the U.S (all but Hawaii), about 99% of all reported cases are confined to just five geographic areas (New England, Mid-Atlantic, East-North Central, South Atlantic, and West North-Central).^[20]

In Europe, cases of B. burgdorferi sensu lato-infected ticks are found predominantly in Norway, Netherlands, Germany, France, Italy, Slovenia, and Poland, but have been isolated in almost every country on the continent. Lyme disease statistics for Europe can be found at Eurosurveillance website.

Borrelia burgdorferi sensu lato-infested ticks are being found more frequently in Japan, as well as in northwest China and far eastern Russia.^[21]^[22] Borrelia has been isolated in Mongolia as well.^[23]

In South America, tick-borne disease recognition and occurrence is rising. Ticks carrying B. burgdorferi sensu lato, as well as canine and human tick-borne disease, have been reported widely in Brazil, but the subspecies of Borrelia has not yet been defined.^[24] The first reported case of Lyme disease in Brazil was made in 1993 in Sao Paulo.^[25] Borrelia burgdorferi sensu stricto antigens in patients have been identified in Colombia and in Bolivia.

In Northern Africa, Borrelia burgdorferi sensu lato has been identified in Morocco, Algeria, Egypt and Tunisia.^[26]^[27]^[28]

In Western Africa and sub-Saharan Africa, tick-borne relapsing fever has been recognized for over a century, since it was first isolated by the British physicians Joseph Dutton and John Todd in 1905. Borrelia in the manifestation of Lyme disease in this region is presently unknown, but evidence indicates the disease may occur in humans in sub-Saharan Africa. The abundance of hosts and tick vectors would favor the establishment of the infection in Africa.^[29] In East Africa two cases of Lyme disease have been reported in Kenya.^[30]

In Australia, there is no definitive evidence for the existence of B. burgdorferi or for any other tick-borne spirochete that may be responsible for a local syndrome being reported as Lyme disease.^[31] Cases of neuroborreliosis have been documented in Australia, but are often ascribed to travel to other continents. The existence of Lyme disease in Australia is controversial.

Life cycle

The life cycle of B. burgdorferi is complex, requiring ticks, rodents, and deer at various points. Mice are the primary reservoir for the bacteria; Ixodes ticks then transmit the B. burgdorferi infection to deer.

Hard ticks have a variety of life histories with respect to optimizing their chance of contact with an appropriate host to ensure survival. The life stages of soft ticks are not readily distinguishable. The first life stage to hatch from the egg, a six-legged larva, takes a blood meal from a host, and molts to the first nymphal stage. Unlike hard ticks, many soft ticks go through multiple nymphal stages, gradually increasing in size until the final molt to the adult stage.

The life cycle of the deer tick comprises three growth stages: the larva, nymph and adult.

The life-cycle concept encompassing reservoirs and infections in multiple hosts has recently been expanded to encompass forms of the spirochete which differ from the motile corkscrew form, and these include cystic spheroplast-like forms, straighted noncoiled bacillary forms which are immotile due to flagellin mutations and granular forms, coccoid in profile. The model of Plasmodium species malaria, with multiple parasitic profiles demonstrable in various host insects and mammals, is a hypothesized model for a similarly complex proposed Borrelia spirochete life cycle.^[32]^[33]

Whereas B. burgdorferi is most associated with deer tick and the white footed mouse,^[34] B. afzelii is most frequently detected in rodent-feeding vector ticks, and B.garinii and B. valaisiana appear to be associated with birds. Both rodents and birds are competent reservoir hosts for Borrelia burgdorferi sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative immune complement system of various host species may determine its reservoir host association.

Genomic characteristics

The genome of B. burgdorferi (B31 strain) was the third microbial genome ever to be sequenced, following the sequencing of both H. influenzae and M. genitalium in 1995, and its chromosome contains 910,725 base pairs and 853 genes.^[35] One of the most striking features of B. burgdorferi as compared with other bacteria is its unusual genome, which is far more complex than that of its spirochetal cousin Treponema pallidum, the agent of syphilis.^[36] In addition to a linear chromosome, the genome of B. burgdorferi strain B31 includes 21 plasmids (12 linear and 9 circular) – by far the largest number of plasmids found in any known bacterium.^[37] Genetic exchange, including plasmid transfers, contributes to the pathogenicity of the organism.^[38] Long-term culture of B. burgdorferi results in a loss of some plasmids and changes in expressed protein profiles. Associated with the loss of plasmids is a loss in the ability of the organism to infect laboratory animals, suggesting the plasmids encode key genes involved in virulence.

Chemical analysis of the external membrane of B. burgdorferi revealed the presence of 46% proteins, 51% lipids and 3% carbohydrates.^[39]

Structure and growth

B. burgdorferi is a highly specialized, motile, two-membrane, flat-waved spirochete, ranging from about 9 to 32 micrometers in length.^[40] Because of its double-membrane envelope, it is often mistakenly described as Gram negative^[41], though it stains weakly in Gram stain. The bacterial membranes in at least the B31, NL303 and N40 strains of B. burgdorferi do not contain lipopolysaccharide, which is extremely atypical for Gram negative bacteria; instead, the membranes contain glycolipids.^[42] However, the membranes in the B31 strain have been found to contain a lipopolysaccharide-like component.^[43] B. burgdorferi is a microaerophilic organism, requiring little oxygen to survive. Unlike most bacteria, B. burgdorferi does not use iron, hence avoiding the difficulty of acquiring iron during infection.^[44] It lives primarily as an extracellular pathogen, although in vitro it can also hide intracellularly (see Mechanisms of persistence section).

Like other spirochetes, such as Treponema pallidum (the agent of syphilis), B. burgdorferi has an axial filament composed of flagella which run lengthways between its cell wall and outer membrane. This structure allows the spirochete to move efficiently in corkscrew fashion through viscous media, such as connective tissue.

B. burgdorferi is very slow growing, with a doubling time of 12–18 hours^[45] (in contrast to pathogens such as Streptococcus and Staphylococcus, which have a doubling time of 20–30 minutes). Since most antibiotics kill bacteria only when they are dividing, this longer doubling time necessitates the use of relatively longer treatment courses for Lyme disease.

Outer surface proteins

The outer membrane of Borrelia burgdorferi is composed of various unique outer surface proteins (Osp) that have been characterized (OspA through OspF). The Osp proteins are lipoproteins anchored by N-terminally-attached fatty acid molecules to the membrane.^[46] They are presumed to play a role in virulence, transmission, or survival in the tick.

OspA, OspB, and OspD are expressed by B. burgdorferi residing in the gut of unfed ticks, suggesting they promote the persistence of the spirochete in ticks between blood meals.^[47]^[48] During transmission to the mammalian host, when the nymphal tick begins to feed and the spirochetes in the midgut begin to multiply rapidly, most spirochetes cease expressing OspA on their surfaces. Simultaneous with the disappearance of OspA, the spirochete population in the midgut begins to express an OspC and migrate to the salivary gland. Upregulation of OspC begins during the first day of feeding and peaks 48 hours after attachment.^[49]

The OspA and OspB genes encode the major outer membrane proteins of the B. burgdorferi. The two Osp proteins show a high degree of sequence similarity, indicating a recent duplication event.^[50] Virtually all spirochetes in the midgut of an unfed nymph tick express OspA. OspA promotes the attachment of B. burgdorferi to the tick protein TROSPA, present on tick gut epithelial cells.^[51] OspB also has an essential role in the adherence of B. burgdorferi to the tick gut.^[52] Although OspD has been shown to bind to tick gut extracts in vitro, as well as OspA and OspB, it is not essential for the attachment and colonization of the tick gut, and it is not required for human infections.^[48]

OspC is a strong antigen; detection of its presence by the host organism stimulates an immune response. While each individual bacterial cell contains just one copy of the ospC gene, the gene sequence of ospC among different strains within each of the three major Lyme disease species is highly variable.^[53] OspC plays an essential role during the early stage of mammalian infection.^[54] In infected ticks feeding on a mammalian host, OspC may also be necessary to allow B. burgdorferi to invade and attach to the salivary gland after leaving the gut, although not all studies agree on such a role for the protein.^[55]^[56] OspC attaches to the tick salivary protein Salp15, which protects the spirochete from complement and impairs the function of dendritic cells.^[57]^[58]^[59]

OspE and OspF were initially identified in B. burgdorferi strain N40.^[60] The ospE and ospF genes are structurally arranged in tandem as one transcriptional unit under the control of a common promoter.^[60] It is now known that individual strains of B. burgdorferi carry multiple related copies of the ospEF locus, which are now collectively referred to as erp (OspE/F-like related protein). In B. burgdoreri strains B31 and 297, most of the erp loci occupy the same position on the multiple copies of the cp32 plasmid present in these strains.^[61] Each erp locus consists of one or two erp genes. When two genes are present, they are transcribed as one operon, although in some cases, an internal promoter in the first gene may also transcribe the second gene.^[62] The presence of multiple Erp proteins was proposed to be important in allowing B. burgdorferi to evade killing by the alternative complement pathway of a broad range of potential animal hosts, as individual Erp proteins exhibited different binding patterns to the complement regulator factor H from different animals.^[63] However, the presence of factor H was recently demonstrated to not be necessary to enable B. burgdorferi to infect mice, suggesting the Erp proteins have an additional function.^[64]

Mechanisms of persistence

While B. burgdorferi is susceptible to a number of antibiotics in vitro, there are contradictory reports as to the efficacy of antibiotics in vivo. B. burgdorferi may persist in humans and animals for months or years. Some studies have suggested persistence of infection despite antibiotic therapy,^[65]^[66]^[67] although others suggested antibiotics rapidly end infections.^[68]^[69]

Various survival strategies of B. burgdorferi have been posited to explain how the pathogen can persist in its host.^[70] including the following:

Physical sequestration of B. burgdorferi in sites less accessible to the immune system and antibiotics, such as the brain^[71] and central nervous system. New evidence suggests that B. burgdorferi may use the host's fibrinolytic system to penetrate the blood–brain barrier.^[72]

Intracellular invasion

B. burgdorferi can invade a variety of cultured cells, including endothelium,^[73] fibroblasts,^[74] lymphocytes,^[75] macrophages,^[76] keratinocytes,^[77] synovium,^[78]^[79] and most recently neuronal and glial cells.^[80] By 'hiding' inside these cells during human infection, B. burgdorferi may be able to evade the immune system and be protected to varying degrees against some antibiotics,^[81]^[82] sometimes allowing the infection to persist. However it remains unknown whether the in vitro observations made with cultured cells are relevant to persistent infection in Lyme disease patients as there have been few reports of intracellular B. burgdorferi in vivo.^[70]

Altered morphological forms, i.e. round bodies (cysts, granules, spheroplasts)

The formation of rounded forms of B. burgdorferi cells, sometimes called spheroplasts, which either lack a cell wall or have a damaged cell wall, has been observed in vitro,^[83]^[84]^[85]^[86] in vivo,^[79]^[87] and in an ex vivo model.^[88] The finding that energy is required for the spiral bacterium to convert to this form^[83] suggests that these altered forms have a survival function, and are not merely end stage degeneration products. Some data suggest these rounded cells are virulent and infectious, are able to survive under adverse environmental conditions, and may revert to the spiral form in vitro, once conditions are more favorable.^[89]^[90] However, rounded cell types triggered by an antibody binding to the OspB surface protein are damaged and dying forms of the bacteria and do not represent a separate form of the organism.^[91]

Compared to the spiral form, spheroplasts of B. burgdorferi have reduced surface area exposed to immune surveillance.^{[citation needed]} They also express some different surface proteins from spirochetes. B. burgdorferi spheroplasts have shown sensitivity in vitro to antiparasitic drugs, such as metronidazole,^[92] tinidazole,^[93] and hydroxychloroquine ^[94] to which the spiral form of B. burgdorferi is not sensitive.

Antigenic variation and gene expression

Like the Borrelia that causes relapsing fever, B. burgdorferi has the ability to vary its surface proteins in response to immune attack.^[70]^[95] This ability is related to the genomic complexity of B. burgdorferi, and is another way B. burgdorferi evades the immune system to establish a chronic infection.^[96]

Immune system suppression.

Complement inhibition, induction of anti-inflammatory cytokines such as IL-10, and the formation of immune complexes have all been documented in B. burgdorferi infection.^[70] Furthermore, the existence of immune complexes may be involved in seronegative acute-phase disease (i.e. false-negative antibody tests of blood and cerebrospinal fluid). One study shows some acute-phase seronegative Lyme patients have antibodies bound up in these complexes.^[97]

Advancing immunology research

The role of T cells in Borrelia was first made in 1984,^[98] the role of cellular immunity in active Lyme disease was made in 1986,^[99] and long term persistence of T cell lymphocyte responses to B. burgdorferi as an "immunological scar syndrome" was hypothesized in 1990.^[100] The role of Th1 and interferon-gamma (IFN-gamma) in Borrelia was first described in 1995.^[101] The cytokine pattern of Lyme disease, and the role of Th1 with down regulation of interleukin-10 (IL-10) was first proposed in 1997.^[102]

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

New research has also found chronic Lyme patients have higher amounts of Borrelia-specific forkhead box P3 (FoxP3) than healthy controls, indicating regulatory T cells might also play a role, by immunosuppression, in the development of chronic Lyme disease. FoxP3 are a specific marker of regulatory T cells.^[103] The signaling pathway P38 mitogen-activated protein kinases (p38 MAP kinase) has also been identified as promoting expression of proinflammatory cytokines from borrelia.^[104]^[105]

The culmination of these new and ongoing immunological studies suggest this cell-mediated immune disruption in the Lyme patient amplifies the inflammatory process, often rendering it chronic and self-perpetuating, regardless of whether the Borrelia bacterium is still present in the host, or in the absence of the inciting pathogen in an autoimmune pattern.^[106]

Vaccines

Due to its universal and high level expression, outer surface protein A (OspA) was the natural focus of early vaccine development efforts. An OspA-based vaccine (LYMErix; SmithKline Beecham) was licensed for use in adults. However, this vaccine was voluntarily removed from the market by its manufacturer in 2002. Recently, considerable progress in the development of broadly protective Lyme disease vaccines has been made. In particular, there is a focus on alternative vaccine candidates that may require fewer boosts and will conceivably provide long term protection. There is interest in developing vaccines that specifically target the tick vectors of Lyme disease, specifically components of tick saliva that coat the bacteria. This approach offers the advantage of protecting against multiple pathogens with one vaccine.^[107] While an effective Lyme disease vaccine seems likely to be developed, earlier experiences with the LYMErix vaccine suggest that bringing such a vaccine to market will be a challenge.^[108]

A vaccine made by Pfizer known as LymeVax is currently available for use in dogs. Having dogs vaccinated should also help to protect their owners from infection by the dog. The vaccine is a 2-strain, multi-antigen vaccime which induces an antibody response to bacterial proteins OspA and OspC.^[109]

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External links

Atlas of Borrelia (images of spirochetal, spheroplast and granular forms)
NCBI Taxonomy Browser – Borrelia
Borrelia burgdorferi B31 Genome Page
Borrelia garinii PBi Genome Page
Borrelia afzelli PKo Genome Page
Schwan TG, Piesman J (2002). "Vector interactions and molecular adaptations of lyme disease and relapsing fever spirochetes associated with transmission by ticks". Emerging Infect. Dis. 8 (2): 115–21. doi:10.3201/eid0802.010198. PMC 2732444. PMID 11897061. {{cite journal}}: Unknown parameter |month= ignored (help)

[Bunikis-a-1] Bunikis J, Garpmo U, Tsao J, Berglund J, Fish D, Barbour AG (2004). "Sequence typing reveals extensive strain diversity of the Lyme borreliosis agents Borrelia burgdorferi in North America and Borrelia afzelii in Europe" (PDF). Microbiology. 150 (Pt 6): 1741–55. doi:10.1099/mic.0.26944-0. PMID 15184561.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[Sherris-2] Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9. {{cite book}}: |author= has generic name (help)

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@@ Line 3: / Line 3: @@
 '''[[Lyme disease]]''', or '''borreliosis''', is caused by [[spirochetal]] [[bacteria]] from the [[genus]] ''[[Borrelia]]'', which has at least 37 known species, 12 of which are Lyme related, and an unknown number of genomic [[strain (biology)|strains]].  ''Borrelia'' [[species]] known to cause Lyme disease are collectively known as ''[[Borrelia burgdorferi]]'' [[sensu lato]].
-''Borrelia'' are [[Microaerophile|microaerophillic]] and slow-growing&mdash;the primary reason for the long delays when diagnosing Lyme disease&mdash;and have been found to have greater [[genetic diversity|strain diversity]] than previously estimated.<ref name="Bunikis-a">{{cite journal | author=Bunikis J, Garpmo U, Tsao J, Berglund J, Fish D, and Barbour AG | title=Sequence typing reveals extensive strain diversity of the Lyme borreliosis agents ''Borrelia burgdorferi'' in North America and ''Borrelia afzelii'' in Europe | journal=Microbiology | year=2004 | pages=1741–55 | volume=150 | issue=Pt 6 | pmid = 15184561 | url=http://mic.sgmjournals.org/cgi/reprint/150/6/1741.pdf | format=PDF | doi=10.1099/mic.0.26944-0}}</ref> The strains differ in clinical symptoms and/or presentation as well as geographic distribution.<ref name=Sherris>{{cite book | author = Ryan KJ and Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th | publisher = McGraw Hill | year = 2004 | isbn = 0-8385-8529-9 }}</ref>
+''Borrelia'' are [[Microaerophile|microaerophillic]] and slow-growing—the primary reason for the long delays when diagnosing Lyme disease—and have been found to have greater [[genetic diversity|strain diversity]] than previously estimated.<ref name="Bunikis-a">{{cite journal | author=Bunikis J, Garpmo U, Tsao J, Berglund J, Fish D, Barbour AG | title=Sequence typing reveals extensive strain diversity of the Lyme borreliosis agents ''Borrelia burgdorferi'' in North America and ''Borrelia afzelii'' in Europe | journal=Microbiology | year=2004 | pages=1741–55 | volume=150 | issue=Pt 6 | pmid = 15184561 | url=http://mic.sgmjournals.org/cgi/reprint/150/6/1741.pdf | format=PDF | doi=10.1099/mic.0.26944-0}}</ref> The strains differ in clinical symptoms and/or presentation as well as geographic distribution.<ref name=Sherris>{{cite book | author = Ryan KJ, Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th | publisher = McGraw Hill | year = 2004 | isbn = 0-8385-8529-9 }}</ref>
 Except for ''[[Borrelia recurrentis]]'' (which causes louse-borne [[relapsing fever]] and is transmitted by the human body louse), all known species are believed to be transmitted by [[tick]]s.<ref>{{cite book | author = Felsenfeld O |title = ''Borrelia'': Strains, Vectors, Human and Animal Borreliosis| location = St. Louis | publisher = Warren H. Green, Inc | year = 1971}}</ref>
@@ Line 13: / Line 13: @@
 ===Emerging genospecies===
-* ''B. valaisiana'' was identified as a genomic species from Strain VS116, and named ''B.&nbsp;valaisiana'' in 1997.<ref>{{cite journal |author=Wang G |title=Genetic and phenotypic analysis of ''Borrelia valaisiana'' sp. nov. (''Borrelia'' genomic groups VS116 and M19) |journal=Int. J. Syst. Bacteriol. |volume=47 |issue=4 |pages=926–932 |year=1997 |pmid=9336888 |doi=10.1099/00207713-47-4-926 |author-separator=, |author2=van Dam AP |author3=Le Fleche A |display-authors=3 |last4=Postic |first4=D. |last5=Peter |first5=O. |last6=Baranton |first6=G. |last7=De Boer |first7=R. |last8=Spanjaard |first8=L. |last9=Dankert |first9=J.}}</ref> It was later detected by [[polymerase chain reaction]] (PCR) in human [[cerebral spinal fluid]] (CSF) in [[Greece]].<ref name="Diza">{{cite journal |author=Diza E, Papa A, Vezyri E, Tsounis S, Milonas I, and Antoniadis A |title=''Borrelia valaisiana'' in cerebrospinal fluid |journal=Emerging Infect. Dis. |volume=10 |issue=9 |pages=1692–1693 |year=2004 |pmid=15503409 |url=http://www.cdc.gov/ncidod/EID/vol10no9/03–0439.htm |format= &ndash; <sup>[http://scholar.google.co.uk/scholar?hl=en&lr=&q=intitle%3A%27%27Borrelia+valaisiana%27%27+in+cerebrospinal+fluid&as_publication=Emerging+Infect.+Dis.&as_ylo=2004&as_yhi=2004&btnG=Search Scholar search]</sup> |pmc=3320289}} {{dead link|date=April 2009}}</ref> ''B. valaisiana'' has been isolated throughout Europe, as well as east Asia.<ref>{{cite journal |author=Masuzawa T |title=Terrestrial distribution of the Lyme borreliosis agent ''Borrelia burgdorferi'' sensu lato in East Asia |journal=Jpn. J. Infect. Dis. |volume=57 |issue=6 |pages=229–235 |year=2004 |pmid=15623946 |doi=}}</ref>
+* ''B. valaisiana'' was identified as a genomic species from Strain VS116, and named ''B.&nbsp;valaisiana'' in 1997.<ref>{{cite journal |author=Wang G |title=Genetic and phenotypic analysis of ''Borrelia valaisiana'' sp. nov. (''Borrelia'' genomic groups VS116 and M19) |journal=Int. J. Syst. Bacteriol. |volume=47 |issue=4 |pages=926–932 |year=1997 |pmid=9336888 |doi=10.1099/00207713-47-4-926 |author-separator=, |author2=van Dam AP |author3=Le Fleche A |display-authors=3 |last4=Postic |first4=D. |last5=Peter |first5=O. |last6=Baranton |first6=G. |last7=De Boer |first7=R. |last8=Spanjaard |first8=L. |last9=Dankert |first9=J.}}</ref> It was later detected by [[polymerase chain reaction]] (PCR) in human [[cerebral spinal fluid]] (CSF) in [[Greece]].<ref name="Diza">{{cite journal |author=Diza E, Papa A, Vezyri E, Tsounis S, Milonas I, Antoniadis A |title=''Borrelia valaisiana'' in cerebrospinal fluid |journal=Emerging Infect. Dis. |volume=10 |issue=9 |pages=1692–3 |year=2004 |pmid=15503409 |url=http://www.cdc.gov/ncidod/EID/vol10no9/03–0439.htm |pmc=3320289}}</ref> ''B. valaisiana'' has been isolated throughout Europe, as well as east Asia.<ref>{{cite journal |author=Masuzawa T |title=Terrestrial distribution of the Lyme borreliosis agent ''Borrelia burgdorferi'' sensu lato in East Asia |journal=Jpn. J. Infect. Dis. |volume=57 |issue=6 |pages=229–235 |year=2004 |pmid=15623946 }}</ref>
 Newly discovered genospecies have also been found to cause disease in humans:
-*''B. lusitaniae'' <ref name="Collares">{{cite journal | author=Collares-Pereira M, Couceiro S, Franca I, Kurtenbach K, Schafer SM, Vitorino L, Goncalves L, Baptista S, Vieira ML, and Cunha C | title=First isolation of ''Borrelia lusitaniae'' from a human patient | journal=J Clin Microbiol | year=2004 | pages=1316–1318 | volume=42 | issue=3 | pmid=15004107 | url=http://jcm.asm.org/cgi/reprint/42/3/1316.pdf | format=PDF | doi=10.1128/JCM.42.3.1316-1318.2004 | pmc=356816}}</ref> in [[Europe]] (especially [[Portugal]]), [[North Africa]] and [[Asia]].
+*''B. lusitaniae'' <ref name="Collares">{{cite journal | author=Collares-Pereira M, Couceiro S, Franca I, Kurtenbach K, Schafer SM, Vitorino L, Goncalves L, Baptista S, Vieira ML, Cunha C | title=First isolation of ''Borrelia lusitaniae'' from a human patient | journal=J Clin Microbiol | year=2004 | pages=1316–8 | volume=42 | issue=3 | pmid=15004107 | url=http://jcm.asm.org/cgi/reprint/42/3/1316.pdf | format=PDF | doi=10.1128/JCM.42.3.1316-1318.2004 | pmc=356816}}</ref> in [[Europe]] (especially [[Portugal]]), [[North Africa]] and [[Asia]].
-*''B. bissettii'' <ref name="Postic">{{cite journal | author=Postic D, Ras NM, Lane RS, Hendson M, and Baranton G | title=Expanded diversity among Californian ''Borrelia'' isolates and description of ''Borrelia bissettii'' sp. nov. (formerly ''Borrelia'' group DN127) | journal=J Clin Microbiol | year=1998 | pages=3497–3504 | volume=36 | issue=12 | pmid=9817861 | url=http://jcm.asm.org/cgi/reprint/36/12/3497.pdf | format=PDF | pmc=105228}}</ref><ref name="Maraspin">{{cite journal | author=Maraspin V, Cimperman J, Lotric-Furlan S, Ruzic-Sabljic E, Jurca T, Picken RN, Strle F | title=Solitary borrelial lymphocytoma in adult patients | journal=Wien Klin Wochenschr | year=2002 | pages=515–523 | volume=114 | issue=13–14 | pmid=12422593}}</ref> in the [[U.S.]] and [[Europe]].
+*''B. bissettii'' <ref name="Postic">{{cite journal | author=Postic D, Ras NM, Lane RS, Hendson M, Baranton G | title=Expanded diversity among Californian ''Borrelia'' isolates and description of ''Borrelia bissettii'' sp. nov. (formerly ''Borrelia'' group DN127) | journal=J Clin Microbiol | year=1998 | pages=3497–3504 | volume=36 | issue=12 | pmid=9817861 | url=http://jcm.asm.org/cgi/reprint/36/12/3497.pdf | format=PDF | pmc=105228}}</ref><ref name="Maraspin">{{cite journal | author=Maraspin V, Cimperman J, Lotric-Furlan S, Ruzic-Sabljic E, Jurca T, Picken RN, Strle F | title=Solitary borrelial lymphocytoma in adult patients | journal=Wien Klin Wochenschr | year=2002 | pages=515–523 | volume=114 | issue=13–14 | pmid=12422593}}</ref> in the [[U.S.]] and [[Europe]].
-*''B.&nbsp;spielmanii'' <ref name="Richter">{{cite journal | author=Richter D, Postic D, Sertour N, Livey I, Matuschka FR, and Baranton G | title=Delineation of ''Borrelia burgdorferi'' sensu lato species by multilocus sequence analysis and confirmation of the delineation of ''Borrelia spielmanii'' sp. nov | journal=Int J Syst Evol Microbiol | year=2006 | pages=873–881 | volume=56 | issue=Pt 4 | pmid=16585709 | doi=10.1099/ijs.0.64050-0}}</ref><ref name="Foldvari">{{cite journal | author=Foldvari G, Farkas R, and Lakos A | title=''Borrelia spielmanii'' erythema migrans, Hungary | journal=Emerg Infect Dis | year=2005 | pages=1794–1795 | volume=11 | issue=11 | pmid=16422006 | url=http://www.cdc.gov/ncidod/EID/vol11no11/05–0542.htm | format= &ndash; <sup>[http://scholar.google.co.uk/scholar?hl=en&lr=&q=intitle%3A%27%27Borrelia+spielmanii%27%27+erythema+migrans%2C+Hungary&as_publication=Emerg+Infect+Dis&as_ylo=2005&as_yhi=2005&btnG=Search Scholar search]</sup> | pmc=3367353}} {{dead link|date=April 2009}}</ref> in [[Europe]].
+*''B.&nbsp;spielmanii'' <ref name="Richter">{{cite journal | author=Richter D, Postic D, Sertour N, Livey I, Matuschka FR, Baranton G | title=Delineation of ''Borrelia burgdorferi'' sensu lato species by multilocus sequence analysis and confirmation of the delineation of ''Borrelia spielmanii'' sp. nov | journal=Int J Syst Evol Microbiol | year=2006 | pages=873–881 | volume=56 | issue=Pt 4 | pmid=16585709 | doi=10.1099/ijs.0.64050-0}}</ref><ref name="Foldvari">{{cite journal | author=Foldvari G, Farkas R, Lakos A | title=''Borrelia spielmanii'' erythema migrans, Hungary | journal=Emerg Infect Dis | year=2005 | pages=1794–5 | volume=11 | issue=11 | pmid=16422006 | url=http://www.cdc.gov/ncidod/EID/vol11no11/05–0542.htm | pmc=3367353}}</ref> in [[Europe]].
 Additional ''B. burgdorferi'' sensu lato genospecies suspected of causing illness, but not confirmed by culture, include ''B.&nbsp;japonica'', ''B.&nbsp;tanukii'' and ''B.&nbsp;turdae'' ([[Japan]]); ''B.&nbsp;sinica'' ([[China]]); and ''B.&nbsp;andersonii'' ([[U.S.]]). Some of these species are carried by ticks not currently recognized as carriers of Lyme disease.
 The ''B.&nbsp;miyamotoi'' spirochete, related to the [[relapsing fever]] group of spirochetes, is also suspected of causing illness in [[Japan]]. Spirochetes similar to ''B. miyamotoi'' have recently been found in both ''[[Ixodes ricinus]]'' ticks in [[Sweden]] and ''I.&nbsp;scapularis'' ticks in the [[U.S.]]<!--
-  --><ref name="Scoles">{{cite journal | author=Scoles GA, Papero M, Beati L, and Fish D | title=A relapsing fever group spirochete transmitted by ''Ixodes scapularis'' ticks | journal=Vector Borne Zoonotic Dis | year=2001 | pages=21–34 | volume=1 | issue=1 | pmid=12653133 | doi=10.1089/153036601750137624}}</ref><!--
+  --><ref name="Scoles">{{cite journal | author=Scoles GA, Papero M, Beati L, Fish D | title=A relapsing fever group spirochete transmitted by ''Ixodes scapularis'' ticks | journal=Vector Borne Zoonotic Dis | year=2001 | pages=21–34 | volume=1 | issue=1 | pmid=12653133 | doi=10.1089/153036601750137624}}</ref><!--
-  --><ref name="Bunikis-b">{{cite journal | author=Bunikis J, Tsao J, Garpmo U, Berglund J, Fish D, and Barbour AG | title=Typing of ''Borrelia'' relapsing fever group strains | journal=Emerg Infect Dis | year=2004 | pages=1661–1664 | volume=10 | issue=9 | pmid=15498172 | pmc=3320305}}</ref><ref>{{Cite news | last = McNeil | first = Donald | title = New Tick-Borne Disease Is Discovered | newspaper = The New York Times| pages = D6| date = 19 September 2011 | url = http://www.nytimes.com/2011/09/20/health/20tick.html| accessdate = 20 September 2011}}</ref>
+  --><ref name="Bunikis-b">{{cite journal | author=Bunikis J, Tsao J, Garpmo U, Berglund J, Fish D, Barbour AG | title=Typing of ''Borrelia'' relapsing fever group strains | journal=Emerg Infect Dis | year=2004 | pages=1661–4 | volume=10 | issue=9 | pmid=15498172 | pmc=3320305}}</ref><ref>{{Cite news | last = McNeil | first = Donald | title = New Tick-Borne Disease Is Discovered | newspaper = The New York Times| pages = D6| date = 19 September 2011 | url = http://www.nytimes.com/2011/09/20/health/20tick.html| accessdate = 20 September 2011}}</ref>
 ===''B. lonestari''===
 Apart from this group of closely related genospecies, additional ''Borrelia'' species of interest include ''B. lonestari'', a spirochete recently detected in the ''Amblyomma americanum'' tick (lone star tick) in the U.S.<!--
-  --><ref name="Varela">{{cite journal | author=Varela AS, Luttrell MP, Howerth EW, Moore VA, Davidson WR, Stallknecht DE, and Little SE | title=First culture isolation of ''Borrelia lonestari'', putative agent of southern tick-associated rash illness | journal=J Clin Microbiol | year=2004 | pages=1163–1169 | volume=42 | issue=3 | pmid=15004069 | url=http://jcm.asm.org/cgi/reprint/42/3/1163.pdf | format=PDF | doi=10.1128/JCM.42.3.1163-1169.2004 | pmc=356874}}</ref><!--
+  --><ref name="Varela">{{cite journal | author=Varela AS, Luttrell MP, Howerth EW, Moore VA, Davidson WR, Stallknecht DE, Little SE | title=First culture isolation of ''Borrelia lonestari'', putative agent of southern tick-associated rash illness | journal=J Clin Microbiol | year=2004 | pages=1163–9 | volume=42 | issue=3 | pmid=15004069 | url=http://jcm.asm.org/cgi/reprint/42/3/1163.pdf | format=PDF | doi=10.1128/JCM.42.3.1163-1169.2004 | pmc=356874}}</ref><!--
 --> ''B. lonestari'' is suspected of causing [[southern tick-associated rash illness]] (STARI), also known as Masters disease in honor of its discoverer, Dr. Edwin Jordan Masters. The illness follows a lone star tick bite, and clinically resembles Lyme disease, but sufferers usually test negative for Lyme.<!--
-  --><ref name="Masters">{{cite journal | author=Masters E, Granter S, Duray P, and Cordes P | title=Physician-diagnosed erythema migrans and erythema migrans-like rashes following Lone Star tick bites | journal=Arch Dermatol | year=1998 | pages=955–960 | volume=134 | issue=8 | pmid=9722725 | doi=10.1001/archderm.134.8.955}}</ref> There is currently no diagnostic test available for STARI/Masters, and no official treatment protocol, though antibiotics are generally prescribed.
+  --><ref name="Masters">{{cite journal | author=Masters E, Granter S, Duray P, Cordes P | title=Physician-diagnosed erythema migrans and erythema migrans-like rashes following Lone Star tick bites | journal=Arch Dermatol | year=1998 | pages=955–960 | volume=134 | issue=8 | pmid=9722725 | doi=10.1001/archderm.134.8.955}}</ref> There is currently no diagnostic test available for STARI/Masters, and no official treatment protocol, though antibiotics are generally prescribed.
 ==Epidemiology==
@@ Line 43: / Line 43: @@
 In [[Europe]], cases of ''B.&nbsp;burgdorferi'' sensu lato-infected ticks are found predominantly in [[Norway]], [[Netherlands]], [[Germany]], [[France]], [[Italy]], [[Slovenia]], and [[Poland]], but have been isolated in almost every country on the continent. Lyme disease statistics for Europe can be found at [http://www.eurosurveillance.org/ew/2006/060622.asp Eurosurveillance website].
-''Borrelia burgdorferi'' sensu lato-infested ticks are being found more frequently in [[Japan]], as well as in northwest [[China]] and far eastern [[Russia]].<ref>{{cite journal |author=Li M, Masuzawa T, Takada N, Ishiguro F, Fujita H, Iwaki A, Wang H, Wang J, Kawabata M, and Yanagihara Y | title=Lyme disease ''Borrelia'' species in northeastern China resemble those isolated from far eastern Russia and Japan | journal=Appl Environ Microbiol | year=1998 | month=July | volume=64 | issue=7 | pages=2705–2709 |pmid=9647853 |pmc=106449}}</ref><ref>{{cite journal | author=Masuzawa T | title=Terrestrial distribution of the Lyme borreliosis agent ''Borrelia burgdorferi'' sensu lato in East Asia | journal=Jpn J Infect Dis. | year=2004 | month=December | volume=57 | issue=6 | pages=229–235 | pmid=15623946}}</ref> ''Borrelia'' has been isolated in Mongolia as well.<ref>{{cite journal | author=Walder G, Lkhamsuren E, Shagdar A, Bataa J, Batmunkh T, Orth D, Heinz FX, Danichova GA, Khasnatinov MA, Wurzner R, and Dierich MP | title=Serological evidence for tick-borne encephalitis, borreliosis, and human granulocytic anaplasmosis in Mongolia | journal=Int J Med Microbiol. | year=2006  | month=May | volume=296  | issue= Suppl 40 | pages=69–75 | doi=10.1016/j.ijmm.2006.01.031 | pmid=16524782}}</ref>
+''Borrelia burgdorferi'' sensu lato-infested ticks are being found more frequently in [[Japan]], as well as in northwest [[China]] and far eastern [[Russia]].<ref>{{cite journal |author=Li M, Masuzawa T, Takada N, Ishiguro F, Fujita H, Iwaki A, Wang H, Wang J, Kawabata M, Yanagihara Y | title=Lyme disease ''Borrelia'' species in northeastern China resemble those isolated from far eastern Russia and Japan | journal=Appl Environ Microbiol | year=1998 | month=July | volume=64 | issue=7 | pages=2705–9 |pmid=9647853 |pmc=106449}}</ref><ref>{{cite journal | author=Masuzawa T | title=Terrestrial distribution of the Lyme borreliosis agent ''Borrelia burgdorferi'' sensu lato in East Asia | journal=Jpn J Infect Dis. | year=2004 | month=December | volume=57 | issue=6 | pages=229–235 | pmid=15623946}}</ref> ''Borrelia'' has been isolated in Mongolia as well.<ref>{{cite journal | author=Walder G, Lkhamsuren E, Shagdar A, Bataa J, Batmunkh T, Orth D, Heinz FX, Danichova GA, Khasnatinov MA, Wurzner R, Dierich MP | title=Serological evidence for tick-borne encephalitis, borreliosis, and human granulocytic anaplasmosis in Mongolia | journal=Int J Med Microbiol. | year=2006  | month=May | volume=296  | issue= Suppl 40 | pages=69–75 | doi=10.1016/j.ijmm.2006.01.031 | pmid=16524782}}</ref>
-In [[South America]], tick-borne disease recognition and occurrence is rising. Ticks carrying ''B. burgdorferi'' sensu lato, as well as canine and human tick-borne disease, have been reported widely in Brazil, but the subspecies of ''Borrelia'' has not yet been defined.<ref>{{cite journal | author=Mantovani E, Costa IP, Gauditano G, Bonoldi VL, Higuchi ML, and Yoshinari NH | title=Description of Lyme disease-like syndrome in Brazil: is it a new tick-borne disease or Lyme disease variation? | journal=Braz J Med Biol Res. | year=2007 | month=April | volume=40 | issue=4 | pages=443–456 | pmid=17401487 | doi=10.1590/S0100-879X2006005000082}}</ref> The first reported case of Lyme disease in Brazil was made in 1993 in [[Sao Paulo]].<ref>{{cite journal | author=Yoshinari NH, Oyafuso LK, Monteiro FG, de Barros PJ, da Cruz FC, Ferreira LG, Bonasser F, Baggio D, and Cossermelli W | title=Lyme disease. Report of a case observed in Brazil | journal=Rev Hosp Clin Fac Med Sao Paulo | year=1993 | month=Jul-Aug | volume=48 | issue=4 | pages=170–174 | pmid=8284588}}</ref> ''Borrelia burgdorferi'' sensu stricto antigens in patients have been identified in [[Colombia]] and in [[Bolivia]].
+In [[South America]], tick-borne disease recognition and occurrence is rising. Ticks carrying ''B. burgdorferi'' sensu lato, as well as canine and human tick-borne disease, have been reported widely in Brazil, but the subspecies of ''Borrelia'' has not yet been defined.<ref>{{cite journal | author=Mantovani E, Costa IP, Gauditano G, Bonoldi VL, Higuchi ML, Yoshinari NH | title=Description of Lyme disease-like syndrome in Brazil: is it a new tick-borne disease or Lyme disease variation? | journal=Braz J Med Biol Res. | year=2007 | month=April | volume=40 | issue=4 | pages=443–456 | pmid=17401487 | doi=10.1590/S0100-879X2006005000082}}</ref> The first reported case of Lyme disease in Brazil was made in 1993 in [[Sao Paulo]].<ref>{{cite journal | author=Yoshinari NH, Oyafuso LK, Monteiro FG, de Barros PJ, da Cruz FC, Ferreira LG, Bonasser F, Baggio D, Cossermelli W | title=Lyme disease. Report of a case observed in Brazil | journal=Rev Hosp Clin Fac Med Sao Paulo | year=1993 | month=Jul-Aug | volume=48 | issue=4 | pages=170–4 | pmid=8284588}}</ref> ''Borrelia burgdorferi'' sensu stricto antigens in patients have been identified in [[Colombia]] and in [[Bolivia]].
-In Northern [[Africa]], ''Borrelia burgdorferi'' sensu lato has been identified in [[Morocco]], [[Algeria]], [[Egypt]] and [[Tunisia]].<ref>{{cite journal | author=Bouattour A, Ghorbel A, Chabchoub A, Postic D | title=Lyme borreliosis situation in North Africa | journal=Arch Inst Pasteur Tunis. | year=2004 | volume=81 | issue=1–4 | pages=13–20 | pmid=16929760}}</ref><ref>{{cite journal | author=Dsouli N, Younsi-Kabachii H, Postic D, Nouira S, Gern L, and Bouattour A | title=Reservoir role of lizard ''Psammodromus algirus'' in transmission cycle of ''Borrelia burgdorferi'' sensu lato (Spirochaetaceae) in Tunisia | journal=J Med Entomol. | year=2006 | month=July | volume=43 | issue=4 | pages=737–742 | doi=10.1603/0022-2585(2006)43[737:RROLPA]2.0.CO;2 | pmid=16892633 | issn=0022-2585}}</ref><ref>{{cite journal | author=Helmy N | title=Seasonal abundance of ''Ornithodoros (O.) savignyi'' and prevalence of infection with ''Borrelia'' spirochetes in Egypt | journal=J Egypt Soc Parasitol | year=2000 | month=August | volume=30 | issue=2 | pages=607–619 | pmid=10946521}}</ref>
+In Northern [[Africa]], ''Borrelia burgdorferi'' sensu lato has been identified in [[Morocco]], [[Algeria]], [[Egypt]] and [[Tunisia]].<ref>{{cite journal | author=Bouattour A, Ghorbel A, Chabchoub A, Postic D | title=Lyme borreliosis situation in North Africa | journal=Arch Inst Pasteur Tunis. | year=2004 | volume=81 | issue=1–4 | pages=13–20 | pmid=16929760}}</ref><ref>{{cite journal | author=Dsouli N, Younsi-Kabachii H, Postic D, Nouira S, Gern L, Bouattour A | title=Reservoir role of lizard ''Psammodromus algirus'' in transmission cycle of ''Borrelia burgdorferi'' sensu lato (Spirochaetaceae) in Tunisia | journal=J Med Entomol. | year=2006 | month=July | volume=43 | issue=4 | pages=737–742 | doi=10.1603/0022-2585(2006)43[737:RROLPA]2.0.CO;2 | pmid=16892633 | issn=0022-2585}}</ref><ref>{{cite journal | author=Helmy N | title=Seasonal abundance of ''Ornithodoros (O.) savignyi'' and prevalence of infection with ''Borrelia'' spirochetes in Egypt | journal=J Egypt Soc Parasitol | year=2000 | month=August | volume=30 | issue=2 | pages=607–619 | pmid=10946521}}</ref>
-In [[Western Africa]] and [[sub-Saharan Africa]], tick-borne [[relapsing fever]] has been recognized for over a century, since it was first isolated by the British physicians Joseph Dutton and John Todd in 1905. ''Borrelia'' in the manifestation of Lyme disease in this region is presently unknown, but evidence indicates the disease may occur in humans in sub-Saharan Africa. The abundance of hosts and tick vectors would favor the establishment of the infection in Africa.<ref>{{cite journal | author=Fivaz BH, Petney TN | title=Lyme disease — a new disease in southern Africa? | journal=J S Afr Vet Assoc. | year=1989 | month=September | volume=60 | issue=3 | pages=155–158 | pmid=2699499}}</ref> In East Africa two cases of Lyme disease have been reported in [[Kenya]].<ref>{{cite journal | author=Jowi JO and Gathua SN | title=Lyme disease: report of two cases | journal=East Afr Med J. | year=2005 | month=May | volume=82 | issue=5 | pages=267–269 | pmid=16119758 | doi=10.4314/eamj.v82i5.9318}}</ref>
+In [[Western Africa]] and [[sub-Saharan Africa]], tick-borne [[relapsing fever]] has been recognized for over a century, since it was first isolated by the British physicians Joseph Dutton and John Todd in 1905. ''Borrelia'' in the manifestation of Lyme disease in this region is presently unknown, but evidence indicates the disease may occur in humans in sub-Saharan Africa. The abundance of hosts and tick vectors would favor the establishment of the infection in Africa.<ref>{{cite journal | author=Fivaz BH, Petney TN | title=Lyme disease — a new disease in southern Africa? | journal=J S Afr Vet Assoc. | year=1989 | month=September | volume=60 | issue=3 | pages=155–8 | pmid=2699499}}</ref> In East Africa two cases of Lyme disease have been reported in [[Kenya]].<ref>{{cite journal | author=Jowi JO, Gathua SN | title=Lyme disease: report of two cases | journal=East Afr Med J. | year=2005 | month=May | volume=82 | issue=5 | pages=267–9 | pmid=16119758 | doi=10.4314/eamj.v82i5.9318}}</ref>
 In [[Australia]], there is no definitive evidence for the existence of ''B.&nbsp;burgdorferi'' or for any other tick-borne spirochete that may be responsible for a local syndrome being reported as Lyme disease.<ref>{{cite journal | author=Piesman J, Stone BF | title=Vector competence of the Australian paralysis tick, ''Ixodes holocyclus'', for the Lyme disease spirochete ''Borrelia burgdorferi''| journal=Int J Parasitol. | year=1991 | month=February | volume=21 | issue=1 | pages=109–111 | pmid=2040556 | doi=10.1016/0020-7519(91)90127-S}}</ref>  Cases of [[neuroborreliosis]] have been documented in Australia, but are often ascribed to travel to other continents. The existence of Lyme disease in Australia is controversial.
@@ Line 62: / Line 62: @@
 The life cycle of the deer tick comprises three growth stages: the [[larva]], [[nymph]] and adult.
-The life-cycle concept encompassing [[Natural reservoir|reservoirs]] and infections in multiple hosts has recently been expanded to encompass forms of the [[spirochete]] which differ from the motile corkscrew form, and these include cystic [[spheroplast|spheroplast-like]] forms, straighted noncoiled bacillary forms which are immotile [[flagellin|due to flagellin mutations]] and granular forms, [[Coccus|coccoid in profile]]. The model of ''Plasmodium'' species [[malaria]], with multiple parasitic profiles demonstrable in various host insects and mammals, is a hypothesized model for a similarly complex proposed ''Borrelia'' spirochete life cycle.<ref>{{cite journal | author=Macdonald AB | title=A life cycle for ''Borrelia'' spirochetes? | journal=Med Hypotheses | year=2006 | volume=67 | issue=4 | pages=810–818 | pmid=16716532 | doi=10.1016/j.mehy.2006.03.028}}</ref><ref>{{cite web | author= | title=Lymeinfo.net — LDAdverseConditions | url=http://www.lymeinfo.net/medical/LDAdverseConditions.pdf | year=2006|format=PDF}}</ref>
+The life-cycle concept encompassing [[Natural reservoir|reservoirs]] and infections in multiple hosts has recently been expanded to encompass forms of the [[spirochete]] which differ from the motile corkscrew form, and these include cystic [[spheroplast|spheroplast-like]] forms, straighted noncoiled bacillary forms which are immotile [[flagellin|due to flagellin mutations]] and granular forms, [[Coccus|coccoid in profile]]. The model of ''Plasmodium'' species [[malaria]], with multiple parasitic profiles demonstrable in various host insects and mammals, is a hypothesized model for a similarly complex proposed ''Borrelia'' spirochete life cycle.<ref>{{cite journal | author=Macdonald AB | title=A life cycle for ''Borrelia'' spirochetes? | journal=Med Hypotheses | year=2006 | volume=67 | issue=4 | pages=810–8 | pmid=16716532 | doi=10.1016/j.mehy.2006.03.028}}</ref><ref>{{cite web | title=Lymeinfo.net — LDAdverseConditions | url=http://www.lymeinfo.net/medical/LDAdverseConditions.pdf | year=2006|format=PDF}}</ref>
-Whereas ''B. burgdorferi'' is most associated with [[Ixodes|deer tick]] and the white footed mouse,<ref>{{cite journal | author=Wallis RC, Brown SE, Kloter KO, and Main AJ Jr. | title=''Erythema chronicum migrans'' and Lyme arthritis: field study of ticks | journal=Am J Epidemiol. | year=1978 | month=October | volume=108 | issue=4 | pages=322–327 | pmid=727201}}</ref> ''B. afzelii'' is most frequently detected in rodent-feeding vector ticks, and ''B.garinii'' and ''B. valaisiana'' appear to be associated with birds. Both rodents and birds are competent reservoir hosts for ''Borrelia burgdorferi'' sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative immune [[complement system]] of various host species may determine its reservoir host association.
+Whereas ''B. burgdorferi'' is most associated with [[Ixodes|deer tick]] and the white footed mouse,<ref>{{cite journal | author=Wallis RC, Brown SE, Kloter KO, Main AJ Jr. | title=''Erythema chronicum migrans'' and Lyme arthritis: field study of ticks | journal=Am J Epidemiol. | year=1978 | month=October | volume=108 | issue=4 | pages=322–7 | pmid=727201}}</ref> ''B. afzelii'' is most frequently detected in rodent-feeding vector ticks, and ''B.garinii'' and ''B. valaisiana'' appear to be associated with birds. Both rodents and birds are competent reservoir hosts for ''Borrelia burgdorferi'' sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative immune [[complement system]] of various host species may determine its reservoir host association.
 ==Genomic characteristics==
-The genome of ''B.&nbsp;burgdorferi'' (B31 strain) was the third microbial genome ever to be sequenced, following the sequencing of both ''H. influenzae'' and ''M. genitalium'' in 1995, and its chromosome contains 910,725 base pairs and 853 genes.<ref name="nature1997">{{cite journal | author=Fraser, Claire M.| title=Genomic sequence of a Lyme disease spirochaete, ''Borrelia burgdorferi'' | journal=Nature | volume=390 | issue=6660 | pages=580–586 | year=1997 | doi=10.1038/37551 | pmid=9403685 | last2=Casjens | first2=S | last3=Huang | first3=WM | last4=Sutton | first4=GG | last5=Clayton | first5=R | last6=Lathigra | first6=R | last7=White | first7=O | last8=Ketchum | first8=KA | last9=Dodson | first9=R }}</ref>
+The genome of ''B.&nbsp;burgdorferi'' (B31 strain) was the third microbial genome ever to be sequenced, following the sequencing of both ''H. influenzae'' and ''M. genitalium'' in 1995, and its chromosome contains 910,725 base pairs and 853 genes.<ref name="nature1997">{{cite journal | author=Fraser, Claire M.| title=Genomic sequence of a Lyme disease spirochaete, ''Borrelia burgdorferi'' | journal=Nature | volume=390 | issue=6660 | pages=580–6 | year=1997 | doi=10.1038/37551 | pmid=9403685 | last2=Casjens | first2=S | last3=Huang | first3=WM | last4=Sutton | first4=GG | last5=Clayton | first5=R | last6=Lathigra | first6=R | last7=White | first7=O | last8=Ketchum | first8=KA | last9=Dodson | first9=R }}</ref>
 One of the most striking features of ''B.&nbsp;burgdorferi'' as compared with other [[bacteria]] is its unusual [[genome]], which is far more complex than that of its spirochetal cousin ''[[Treponema pallidum]]'', the agent of [[syphilis]].<!--
-  --><ref name="Porcella">{{cite journal | author=Porcella SF and Schwan TG | title=''Borrelia burgdorferi'' and ''Treponema pallidum'': a comparison of functional genomics, environmental adaptations, and pathogenic mechanisms | journal=J Clin Invest | year=2001 | pages=651–6 | volume=107 | issue=6 | pmid=11254661 | url=http://www.jci.org/cgi/content/full/107/6/651 | doi=10.1172/JCI12484 | pmc=208952}}</ref>
+  --><ref name="Porcella">{{cite journal | author=Porcella SF, Schwan TG | title=''Borrelia burgdorferi'' and ''Treponema pallidum'': a comparison of functional genomics, environmental adaptations, and pathogenic mechanisms | journal=J Clin Invest | year=2001 | pages=651–6 | volume=107 | issue=6 | pmid=11254661 | url=http://www.jci.org/cgi/content/full/107/6/651 | doi=10.1172/JCI12484 | pmc=208952}}</ref>
 In addition to a linear chromosome, the genome of ''B.&nbsp;burgdorferi'' strain B31 includes 21 [[plasmid]]s (12 linear and 9 circular) – by far the largest number of plasmids found in any known bacterium.<!--
-  --><ref name="Casjens">{{cite journal | author=Casjens S, Palmer N, van Vugt R, Huang WM, Stevenson B, Rosa P, Lathigra R, Sutton G, Peterson J, Dodson RJ, Haft D, Hickey E, Gwinn M, White O, and Fraser CM | title=A bacterial genome in flux: the twelve linear and nine circular extrachromosomal DNAs in an infectious isolate of the Lyme disease spirochete ''Borrelia burgdorferi'' | journal=Mol Microbiol | year=2000 | pages=490–516 | volume=35 | issue=3 | pmid=10672174 | url=http://www.blackwell-synergy.com/doi/full/10.1046/j.1365-2958.2000.01698.x | doi=10.1046/j.1365-2958.2000.01698.x}}</ref>
+  --><ref name="Casjens">{{cite journal | author=Casjens S, Palmer N, van Vugt R, Huang WM, Stevenson B, Rosa P, Lathigra R, Sutton G, Peterson J, Dodson RJ, Haft D, Hickey E, Gwinn M, White O, Fraser CM | title=A bacterial genome in flux: the twelve linear and nine circular extrachromosomal DNAs in an infectious isolate of the Lyme disease spirochete ''Borrelia burgdorferi'' | journal=Mol Microbiol | year=2000 | pages=490–516 | volume=35 | issue=3 | pmid=10672174 | url=http://www.blackwell-synergy.com/doi/full/10.1046/j.1365-2958.2000.01698.x | doi=10.1046/j.1365-2958.2000.01698.x}}</ref>
 Genetic exchange, including plasmid transfers, contributes to the [[pathogenicity]] of the organism.<!--
-  --><ref name="Qiu">{{cite journal | author=Qiu WG, Schutzer SE, Bruno JF, Attie O, Xu Y, Dunn JJ, Fraser CM, Casjens SR, and Luft BJ | title=Genetic exchange and plasmid transfers in ''Borrelia burgdorferi'' sensu stricto revealed by three-way genome comparisons and multilocus sequence typing | journal=Proc Natl Acad Sci USA | year=2004 | pages=14150–5 | volume=101 | issue=39 | pmid=15375210 | url=http://www.pnas.org/cgi/reprint/101/39/14150.pdf | format=PDF | doi=10.1073/pnas.0402745101 | pmc=521097}}</ref>
+  --><ref name="Qiu">{{cite journal | author=Qiu WG, Schutzer SE, Bruno JF, Attie O, Xu Y, Dunn JJ, Fraser CM, Casjens SR, Luft BJ | title=Genetic exchange and plasmid transfers in ''Borrelia burgdorferi'' sensu stricto revealed by three-way genome comparisons and multilocus sequence typing | journal=Proc Natl Acad Sci USA | year=2004 | pages=14150–5 | volume=101 | issue=39 | pmid=15375210 | url=http://www.pnas.org/cgi/reprint/101/39/14150.pdf | format=PDF | doi=10.1073/pnas.0402745101 | pmc=521097}}</ref>
 Long-term culture of ''B.&nbsp;burgdorferi'' results in a loss of some plasmids and changes in expressed protein profiles. Associated with the loss of plasmids is a loss in the ability of the organism to infect laboratory animals, suggesting the plasmids encode key genes involved in [[virulence]].
@@ Line 79: / Line 79: @@
 ==Structure and growth==
-''B. burgdorferi'' is a highly specialized, motile, two-membrane, flat-waved [[spirochete]], ranging from about 9 to 32 micrometers in length.<ref name="pmid8159765">{{cite journal |author=Goldstein SF, Charon NW, and Kreiling JA |title=''Borrelia burgdorferi'' swims with a planar waveform similar to that of eukaryotic flagella |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue=8 |pages=3433–3437 |year=1994 |pmid=8159765 |doi=10.1073/pnas.91.8.3433 |pmc=43591}}</ref> Because of its double-membrane envelope, it is often mistakenly described as [[Gram negative]]<ref>{{cite book |author= Samuels DS; Radolf, JD (editors)| year=2010 |title=Borrelia: Molecular Biology, Host Interaction and Pathogenesis | publisher=Caister Academic Press | isbn= 978-1-904455-58-5 | chapter=Chapter 6, Structure, Function and Biogenesis of the ''Borrelia'' Cell Envelope}}</ref>, though it stains weakly in [[Gram stain]]. The bacterial membranes in at least the B31, NL303 and N40 strains of ''B.&nbsp;burgdorferi'' do not contain [[lipopolysaccharide]], which is extremely atypical for Gram negative bacteria; instead, the membranes contain [[glycolipids]].<ref name="pmid12799465">{{cite journal |author=Ben-Menachem G, Kubler-Kielb J, Coxon B, Yergey A, and Schneerson R |title=A newly discovered cholesteryl galactoside from ''Borrelia burgdorferi'' |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue=13 |pages=7913–7918 |year=2003 |pmid=12799465 |doi=10.1073/pnas.1232451100 |pmc=164687}}</ref>  However, the membranes in the B31 strain have been found to contain a lipopolysaccharide-like component.<ref name="schwarzova">{{cite journal | author=Schwarzová K and Čižnár I | title=Immunochemical analysis of lipopolysaccharide-like component extracted from ''Borrelia burgdorferi'' sensu lato | journal=Folia Microbiol. | volume=49 | issue=5 | pages=625–629 | year=2004 | url = http://www.cssm.info/priloha/fm2004_625.pdf
+''B. burgdorferi'' is a highly specialized, motile, two-membrane, flat-waved [[spirochete]], ranging from about 9 to 32 micrometers in length.<ref name="pmid8159765">{{cite journal |author=Goldstein SF, Charon NW, Kreiling JA |title=''Borrelia burgdorferi'' swims with a planar waveform similar to that of eukaryotic flagella |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue=8 |pages=3433–7 |year=1994 |pmid=8159765 |doi=10.1073/pnas.91.8.3433 |pmc=43591}}</ref> Because of its double-membrane envelope, it is often mistakenly described as [[Gram negative]]<ref>{{cite book |author= Samuels DS; Radolf, JD (editors)| year=2010 |title=Borrelia: Molecular Biology, Host Interaction and Pathogenesis | publisher=Caister Academic Press | isbn= 978-1-904455-58-5 | chapter=Ch. 6: Structure, Function and Biogenesis of the ''Borrelia'' Cell Envelope}}</ref>, though it stains weakly in [[Gram stain]]. The bacterial membranes in at least the B31, NL303 and N40 strains of ''B.&nbsp;burgdorferi'' do not contain [[lipopolysaccharide]], which is extremely atypical for Gram negative bacteria; instead, the membranes contain [[glycolipids]].<ref name="pmid12799465">{{cite journal |author=Ben-Menachem G, Kubler-Kielb J, Coxon B, Yergey A, Schneerson R |title=A newly discovered cholesteryl galactoside from ''Borrelia burgdorferi'' |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue=13 |pages=7913–8 |year=2003 |pmid=12799465 |doi=10.1073/pnas.1232451100 |pmc=164687}}</ref>  However, the membranes in the B31 strain have been found to contain a lipopolysaccharide-like component.<ref name="schwarzova">{{cite journal | author=Schwarzová K, Čižnár I | title=Immunochemical analysis of lipopolysaccharide-like component extracted from ''Borrelia burgdorferi'' sensu lato | journal=Folia Microbiol. | volume=49 | issue=5 | pages=625–9 | year=2004 | url = http://www.cssm.info/priloha/fm2004_625.pdf
-| accessdate = 2007-10-26|format=PDF | doi=10.1007/BF02931545}}</ref> ''B.&nbsp;burgdorferi'' is a [[microaerophilic]] organism, requiring little oxygen to survive.  Unlike most bacteria, ''B. burgdorferi'' does not use iron, hence avoiding the difficulty of acquiring iron during infection.<ref name="pmid10834845">{{cite journal |author=Posey JE and Gherardini FC |title=Lack of a role for iron in the Lyme disease pathogen |journal=Science |volume=288 |issue=5471 |pages=1651–3 |year=2000 |pmid=10834845 |doi=10.1126/science.288.5471.1651}}</ref>  It lives primarily as an [[extracellular]] pathogen, although ''in vitro'' it can also hide [[intracellular]]ly (see [[#Mechanisms of persistence|Mechanisms of persistence]] section).
+| accessdate = 2007-10-26|format=PDF | doi=10.1007/BF02931545}}</ref> ''B.&nbsp;burgdorferi'' is a [[microaerophilic]] organism, requiring little oxygen to survive.  Unlike most bacteria, ''B. burgdorferi'' does not use iron, hence avoiding the difficulty of acquiring iron during infection.<ref name="pmid10834845">{{cite journal |author=Posey JE, Gherardini FC |title=Lack of a role for iron in the Lyme disease pathogen |journal=Science |volume=288 |issue=5471 |pages=1651–3 |year=2000 |pmid=10834845 |doi=10.1126/science.288.5471.1651}}</ref>  It lives primarily as an [[extracellular]] pathogen, although ''in vitro'' it can also hide [[intracellular]]ly (see [[#Mechanisms of persistence|Mechanisms of persistence]] section).
 Like other spirochetes, such as ''[[Treponema pallidum]]'' (the agent of [[syphilis]]), ''B. burgdorferi'' has an axial filament composed of [[flagella]] which run lengthways between its cell wall and outer membrane. This structure allows the spirochete to move efficiently in corkscrew fashion through [[viscous]] media, such as [[connective tissue]].
-''B. burgdorferi'' is very slow growing, with a doubling time of 12–18 hours<ref>{{cite book | author=Kelly, RT | year=1984 | title=Genus IV. Borrelia Swellengrebel 1907, 582AL | booktitle=Bergey's Manual of Systematic Bacteriology | volume=1 | pages=57–62 | editor=Krieg NR and Holt JG | publisher=Williams & Wilkins: Baltimore}}</ref> (in contrast to pathogens such as ''[[Streptococcus]]'' and ''[[Staphylococcus]]'', which have a doubling time of 20–30 minutes). Since most [[antibiotics]] kill bacteria only when they are dividing, this longer doubling time necessitates the use of relatively longer treatment courses for Lyme disease.
+''B. burgdorferi'' is very slow growing, with a doubling time of 12–18 hours<ref>{{cite book | author=Kelly, RT | year=1984 | title=Genus IV. Borrelia Swellengrebel 1907, 582AL | booktitle=Bergey's Manual of Systematic Bacteriology | volume=1 | pages=57–62 | editor=Krieg NR, Holt JG | publisher=Williams & Wilkins: Baltimore}}</ref> (in contrast to pathogens such as ''[[Streptococcus]]'' and ''[[Staphylococcus]]'', which have a doubling time of 20–30 minutes). Since most [[antibiotics]] kill bacteria only when they are dividing, this longer doubling time necessitates the use of relatively longer treatment courses for Lyme disease.
 ==Outer surface proteins==
-The outer membrane of ''Borrelia burgdorferi'' is composed of various unique outer surface [[lipoproteins|proteins]] (Osp) that have been characterized (OspA through OspF). The Osp proteins are [[lipoproteins]] anchored by N-terminally-attached fatty acid molecules to the membrane.<ref name="pmid10878114">{{cite journal |author=Haake DA |title=Spirochaetal lipoproteins and pathogenesis |journal=Microbiology (Reading, Engl.) |volume=146 |issue= 7|pages=1491–1504 |year=2000 |pmid=10878114 |doi= |pmc=2664406}}</ref>  They are presumed to play a role in virulence, transmission, or survival in the tick.
+The outer membrane of ''Borrelia burgdorferi'' is composed of various unique outer surface [[lipoproteins|proteins]] (Osp) that have been characterized (OspA through OspF). The Osp proteins are [[lipoproteins]] anchored by N-terminally-attached fatty acid molecules to the membrane.<ref name="pmid10878114">{{cite journal |author=Haake DA |title=Spirochaetal lipoproteins and pathogenesis |journal=Microbiology (Reading, Engl.) |volume=146 |issue= 7|pages=1491–1504 |year=2000 |pmid=10878114 |pmc=2664406}}</ref>  They are presumed to play a role in virulence, transmission, or survival in the tick.
-OspA, OspB, and OspD are expressed by ''B. burgdorferi'' residing in the gut of unfed ticks, suggesting they promote the persistence of the spirochete in ticks between blood meals.<ref name="pmid7708747">{{cite journal |author=Schwan TG, Piesman J, Golde WT, Dolan MC, and Rosa PA |title=Induction of an outer surface protein on ''Borrelia burgdorferi'' during tick feeding |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue=7 |pages=2909–2913 |year=1995 |pmid=7708747 |doi=10.1073/pnas.92.7.2909 |pmc=42328}}</ref><ref name="Li 2007">{{cite journal |author=Li X, Neelakanta G, Liu X, Beck DS, Kantor FS, Fish D, Anderson JF, and Fikrig E |title=Role of outer surface protein D in the ''Borrelia burgdorferi'' life cycle |journal=Infect. Immun. |volume=75 |issue=9 |pages=4237–4244 |year=2007 |pmid=17620358 |doi=10.1128/IAI.00632-07 |pmc=1951184}}</ref>  During transmission to the mammalian host, when the nymphal tick begins to feed and the spirochetes in the midgut begin to multiply rapidly, most spirochetes cease expressing OspA on their surfaces. Simultaneous with the disappearance of OspA, the spirochete population in the midgut begins to express an OspC and migrate to the salivary gland. Upregulation of OspC begins during the first day of feeding and peaks 48 hours after attachment.<ref>{{cite journal | author=Schwan TG and Piesman J | title=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 | journal=J Clin Microbiol | year=2000 | volume=38 | pages=382–388 | pmid=10618120 | issue=1 | pmc=88728}}</ref>
+OspA, OspB, and OspD are expressed by ''B. burgdorferi'' residing in the gut of unfed ticks, suggesting they promote the persistence of the spirochete in ticks between blood meals.<ref name="pmid7708747">{{cite journal |author=Schwan TG, Piesman J, Golde WT, Dolan MC, Rosa PA |title=Induction of an outer surface protein on ''Borrelia burgdorferi'' during tick feeding |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue=7 |pages=2909–13 |year=1995 |pmid=7708747 |doi=10.1073/pnas.92.7.2909 |pmc=42328}}</ref><ref name="Li 2007">{{cite journal |author=Li X, Neelakanta G, Liu X, Beck DS, Kantor FS, Fish D, Anderson JF, Fikrig E |title=Role of outer surface protein D in the ''Borrelia burgdorferi'' life cycle |journal=Infect. Immun. |volume=75 |issue=9 |pages=4237–44 |year=2007 |pmid=17620358 |doi=10.1128/IAI.00632-07 |pmc=1951184}}</ref>  During transmission to the mammalian host, when the nymphal tick begins to feed and the spirochetes in the midgut begin to multiply rapidly, most spirochetes cease expressing OspA on their surfaces. Simultaneous with the disappearance of OspA, the spirochete population in the midgut begins to express an OspC and migrate to the salivary gland. Upregulation of OspC begins during the first day of feeding and peaks 48 hours after attachment.<ref>{{cite journal | author=Schwan TG, Piesman J | title=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 | journal=J Clin Microbiol | year=2000 | volume=38 | pages=382–8 | pmid=10618120 | issue=1 | pmc=88728}}</ref>
-The OspA and OspB genes encode the major outer membrane proteins of the ''B.&nbsp;burgdorferi''.  The two Osp proteins show a high degree of sequence similarity, indicating a recent duplication event.<ref name="pmid2761388">{{cite journal |author=Bergström S, Bundoc VG, and Barbour AG |title=Molecular analysis of linear plasmid-encoded major surface proteins, OspA and OspB, of the Lyme disease spirochaete ''Borrelia burgdorferi'' |journal=Mol. Microbiol. |volume=3 |issue=4 |pages=479–486 |year=1989 |pmid=2761388 |doi=10.1111/j.1365-2958.1989.tb00194.x}}</ref>  Virtually all [[spirochetes]] in the midgut of an unfed nymph tick express OspA. OspA promotes the attachment of ''B. burgdorferi'' to the tick protein TROSPA, present on tick gut epithelial cells.<ref name="pmid15537536">{{cite journal |author=Pal U, Li X, Wang T, Montgomery RR, Ramamoorthi N, Desilva AM, Bao F, Yang X, Pypaert M, Pradhan D, Kantor FS, Telford S, Anderson JF, and Fikrig E |title=TROSPA, an ''Ixodes scapularis'' receptor for ''Borrelia burgdorferi'' |journal=Cell |volume=119 |issue=4 |pages=457–468 |year=2004 |pmid=15537536 |doi=10.1016/j.cell.2004.10.027}}</ref>  OspB also has an essential role in the adherence of ''B. burgdorferi'' to the tick gut.<ref name="pmid17352535">{{cite journal |author=Neelakanta G, Li X, Pal U, Liu X, Beck DS, DePonte K, Fish D, Kantor FS, and Fikrig E |title=Outer surface protein B is critical for ''Borrelia burgdorferi'' adherence and survival within Ixodes ticks |journal=PLoS Pathog. |volume=3 |issue=3 |pages=e33 |year=2007 |pmid=17352535 |doi=10.1371/journal.ppat.0030033 |pmc=1817655}}</ref>  Although OspD has been shown to bind to tick gut extracts ''in vitro'', as well as OspA and OspB, it is not essential for the attachment and colonization of the tick gut, and it is not required for human infections.<ref name="Li 2007"/>
+The OspA and OspB genes encode the major outer membrane proteins of the ''B.&nbsp;burgdorferi''.  The two Osp proteins show a high degree of sequence similarity, indicating a recent duplication event.<ref name="pmid2761388">{{cite journal |author=Bergström S, Bundoc VG, Barbour AG |title=Molecular analysis of linear plasmid-encoded major surface proteins, OspA and OspB, of the Lyme disease spirochaete ''Borrelia burgdorferi'' |journal=Mol. Microbiol. |volume=3 |issue=4 |pages=479–486 |year=1989 |pmid=2761388 |doi=10.1111/j.1365-2958.1989.tb00194.x}}</ref>  Virtually all [[spirochetes]] in the midgut of an unfed nymph tick express OspA. OspA promotes the attachment of ''B. burgdorferi'' to the tick protein TROSPA, present on tick gut epithelial cells.<ref name="pmid15537536">{{cite journal |author=Pal U, Li X, Wang T, Montgomery RR, Ramamoorthi N, Desilva AM, Bao F, Yang X, Pypaert M, Pradhan D, Kantor FS, Telford S, Anderson JF, Fikrig E |title=TROSPA, an ''Ixodes scapularis'' receptor for ''Borrelia burgdorferi'' |journal=Cell |volume=119 |issue=4 |pages=457–468 |year=2004 |pmid=15537536 |doi=10.1016/j.cell.2004.10.027}}</ref>  OspB also has an essential role in the adherence of ''B. burgdorferi'' to the tick gut.<ref name="pmid17352535">{{cite journal |author=Neelakanta G, Li X, Pal U, Liu X, Beck DS, DePonte K, Fish D, Kantor FS, Fikrig E |title=Outer surface protein B is critical for ''Borrelia burgdorferi'' adherence and survival within Ixodes ticks |journal=PLoS Pathog. |volume=3 |issue=3 |pages=e33 |year=2007 |pmid=17352535 |doi=10.1371/journal.ppat.0030033 |pmc=1817655}}</ref>  Although OspD has been shown to bind to tick gut extracts ''in vitro'', as well as OspA and OspB, it is not essential for the attachment and colonization of the tick gut, and it is not required for human infections.<ref name="Li 2007"/>
-OspC is a strong [[antigen]]; detection of its presence by the host organism stimulates an immune response. While each individual bacterial cell contains just one copy of the ''ospC'' gene, the gene sequence of ''ospC'' among different strains within each of the three major Lyme disease species is highly variable.<ref name="Baranton 2001">{{cite journal |author=Baranton G, Seinost G, Theodore G, Postic D, Dykhuizen D |title=Distinct levels of genetic diversity of ''Borrelia burgdorferi'' are associated with different aspects of pathogenicity |journal=Res. Microbiol. |volume=152 |issue=2 |pages=149–56 |year=2001 |month=March |pmid=11316368 |doi= 10.1016/S0923-2508(01)01186-X|url=http://linkinghub.elsevier.com/retrieve/pii/S092325080101186X}}</ref> OspC plays an essential role during the early stage of mammalian infection.<ref name="Tilly 2006">{{cite journal |author=Tilly K, Krum JG, Bestor A, Jewett MW, Grimm D, Bueschel D, Byram R, Dorward D, Vanraden MJ, Stewart P, Rosa P |title=''Borrelia burgdorferi'' OspC protein required exclusively in a crucial early stage of mammalian infection |journal=Infect. Immun. |volume=74 |issue=6 |pages=3554–64 |year=2006 |month=June |pmid=16714588 |pmc=1479285 |doi=10.1128/IAI.01950-05 |url=}}</ref>  In infected ticks feeding on a mammalian host, OspC may also be necessary to allow ''B. burgdorferi'' to invade and attach to the salivary gland after leaving the gut, although not all studies agree on such a role for the protein.<ref name="Pal 2004">{{cite journal |author=Pal U, Yang X, Chen M, Bockenstedt LK, Anderson JF, Flavell RA, Norgard MV, Fikrig E |title=OspC facilitates ''Borrelia burgdorferi'' invasion of ''Ixodes scapularis'' salivary glands |journal=J. Clin. Invest. |volume=113 |issue=2 |pages=220–30 |year=2004 |month=January |pmid=14722614 |pmc=311436 |doi=10.1172/JCI19894 |url=}}</ref><ref name="Grimm 2004">{{cite journal |author=Grimm D, Tilly K, Byram R, Stewart PE, Krum JG, Bueschel DM, Schwan TG, Policastro PF, Elias AF, Rosa PA |title=Outer-surface protein C of the Lyme disease spirochete: a protein induced in ticks for infection of mammals |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue=9 |pages=3142–7 |year=2004 |month=March |pmid=14970347 |pmc=365757 |doi=10.1073/pnas.0306845101 |url=}}</ref>  OspC attaches to the tick salivary protein Salp15, which protects the spirochete from [[Complement system|complement]] and impairs the function of [[dendritic cells]].<ref name="Ramamoorthi 2005">{{cite journal |author=Ramamoorthi N, Narasimhan S, Pal U, Bao F, Yang XF, Fish D, Anguita J, Norgard MV, Kantor FS, Anderson JF, Koski RA, Fikrig E |title=The Lyme disease agent exploits a tick protein to infect the mammalian host |journal=Nature |volume=436 |issue=7050 |pages=573–7 |year=2005 |month=July |pmid=16049492 |doi=10.1038/nature03812 |url=}}</ref><ref name="Schuijt 2008">{{cite journal |author=Schuijt TJ, Hovius JW, van Burgel ND, Ramamoorthi N, Fikrig E, van Dam AP |title=The tick salivary protein Salp15 inhibits the killing of serum-sensitive ''Borrelia burgdorferi'' sensu lato isolates |journal=Infect. Immun. |volume=76 |issue=7 |pages=2888–94 |year=2008 |month=July |pmid=18426890 |pmc=2446733 |doi=10.1128/IAI.00232-08 |url=}}</ref><ref name="Hovius 2008">{{cite journal |author=Hovius JW, de Jong MA, den Dunnen J, Litjens M, Fikrig E, van der Poll T, Gringhuis SI, Geijtenbeek TB |title=Salp15 binding to DC-SIGN inhibits cytokine expression by impairing both nucleosome remodeling and mRNA stabilization |journal=PLoS Pathog. |volume=4 |issue=2 |pages=e31 |year=2008 |month=February |pmid=18282094 |pmc=2242833 |doi=10.1371/journal.ppat.0040031 |url=}}</ref>
+OspC is a strong [[antigen]]; detection of its presence by the host organism stimulates an immune response. While each individual bacterial cell contains just one copy of the ''ospC'' gene, the gene sequence of ''ospC'' among different strains within each of the three major Lyme disease species is highly variable.<ref name="Baranton 2001">{{cite journal |author=Baranton G, Seinost G, Theodore G, Postic D, Dykhuizen D |title=Distinct levels of genetic diversity of ''Borrelia burgdorferi'' are associated with different aspects of pathogenicity |journal=Res. Microbiol. |volume=152 |issue=2 |pages=149–56 |year=2001 |month=March |pmid=11316368 |doi= 10.1016/S0923-2508(01)01186-X|url=http://linkinghub.elsevier.com/retrieve/pii/S092325080101186X}}</ref> OspC plays an essential role during the early stage of mammalian infection.<ref name="Tilly 2006">{{cite journal |author=Tilly K, Krum JG, Bestor A, Jewett MW, Grimm D, Bueschel D, Byram R, Dorward D, Vanraden MJ, Stewart P, Rosa P |title=''Borrelia burgdorferi'' OspC protein required exclusively in a crucial early stage of mammalian infection |journal=Infect. Immun. |volume=74 |issue=6 |pages=3554–64 |year=2006 |month=June |pmid=16714588 |pmc=1479285 |doi=10.1128/IAI.01950-05 }}</ref>  In infected ticks feeding on a mammalian host, OspC may also be necessary to allow ''B. burgdorferi'' to invade and attach to the salivary gland after leaving the gut, although not all studies agree on such a role for the protein.<ref name="Pal 2004">{{cite journal |author=Pal U, Yang X, Chen M, Bockenstedt LK, Anderson JF, Flavell RA, Norgard MV, Fikrig E |title=OspC facilitates ''Borrelia burgdorferi'' invasion of ''Ixodes scapularis'' salivary glands |journal=J. Clin. Invest. |volume=113 |issue=2 |pages=220–30 |year=2004 |month=January |pmid=14722614 |pmc=311436 |doi=10.1172/JCI19894 }}</ref><ref name="Grimm 2004">{{cite journal |author=Grimm D, Tilly K, Byram R, Stewart PE, Krum JG, Bueschel DM, Schwan TG, Policastro PF, Elias AF, Rosa PA |title=Outer-surface protein C of the Lyme disease spirochete: a protein induced in ticks for infection of mammals |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue=9 |pages=3142–7 |year=2004 |month=March |pmid=14970347 |pmc=365757 |doi=10.1073/pnas.0306845101 }}</ref>  OspC attaches to the tick salivary protein Salp15, which protects the spirochete from [[Complement system|complement]] and impairs the function of [[dendritic cells]].<ref name="Ramamoorthi 2005">{{cite journal |author=Ramamoorthi N, Narasimhan S, Pal U, Bao F, Yang XF, Fish D, Anguita J, Norgard MV, Kantor FS, Anderson JF, Koski RA, Fikrig E |title=The Lyme disease agent exploits a tick protein to infect the mammalian host |journal=Nature |volume=436 |issue=7050 |pages=573–7 |year=2005 |month=July |pmid=16049492 |doi=10.1038/nature03812 }}</ref><ref name="Schuijt 2008">{{cite journal |author=Schuijt TJ, Hovius JW, van Burgel ND, Ramamoorthi N, Fikrig E, van Dam AP |title=The tick salivary protein Salp15 inhibits the killing of serum-sensitive ''Borrelia burgdorferi'' sensu lato isolates |journal=Infect. Immun. |volume=76 |issue=7 |pages=2888–94 |year=2008 |month=July |pmid=18426890 |pmc=2446733 |doi=10.1128/IAI.00232-08 }}</ref><ref name="Hovius 2008">{{cite journal |author=Hovius JW, de Jong MA, den Dunnen J, Litjens M, Fikrig E, van der Poll T, Gringhuis SI, Geijtenbeek TB |title=Salp15 binding to DC-SIGN inhibits cytokine expression by impairing both nucleosome remodeling and mRNA stabilization |journal=PLoS Pathog. |volume=4 |issue=2 |pages=e31 |year=2008 |month=February |pmid=18282094 |pmc=2242833 |doi=10.1371/journal.ppat.0040031 }}</ref>
-OspE and OspF were initially identified in ''B. burgdorferi'' strain N40.<ref name="Lam 1994">{{cite journal |author=Lam TT, Nguyen TP, Montgomery RR, Kantor FS, Fikrig E, and Flavell RA |title=Outer surface proteins E and F of ''Borrelia burgdorferi'', the agent of Lyme disease |journal=Infect. Immun. |volume=62 |issue=1 |pages=290–298 |year=1994 |pmid=8262642 |doi= |pmc=186099}}</ref>  The ''ospE'' and ''ospF'' genes are structurally arranged in tandem as one transcriptional unit under the control of a common promoter.<ref name="Lam 1994"/>  It is now known that individual strains of ''B. burgdorferi'' carry multiple related copies of the ''ospEF'' locus, which are now collectively referred to as ''erp'' (Osp''E''/F-like ''r''elated ''p''rotein).  In ''B. burgdoreri'' strains B31 and 297, most of the ''erp'' loci occupy the same position on the multiple copies of the cp32 plasmid present in these strains.<ref name="pmid11075913">{{cite journal |author=Stevenson B, Zückert WR, and Akins DR |title=Repetition, conservation, and variation: the multiple cp32 plasmids of ''Borrelia'' species |journal=J. Mol. Microbiol. Biotechnol. |volume=2 |issue=4 |pages=411–422 |year=2000 |pmid=11075913 |doi=}}</ref>  Each ''erp'' locus consists of one or two ''erp'' genes.  When two genes are present, they are transcribed as one [[operon]], although in some cases, an internal promoter in the first gene may also transcribe the second gene.<ref name="pmid9596729">{{cite journal |author=Stevenson B, Bono JL, Schwan TG, and Rosa P |title=''Borrelia burgdorferi'' Erp proteins are immunogenic in mammals infected by tick bite, and their synthesis is inducible in cultured bacteria |journal=Infect. Immun. |volume=66 |issue=6 |pages=2648–2654 |year=1998 |pmid=9596729 |doi= |pmc=108251}}</ref>  The presence of multiple Erp proteins was proposed to be important in allowing ''B. burgdorferi'' to evade killing by the [[alternative complement pathway]] of a broad range of potential animal hosts, as individual Erp proteins exhibited different binding patterns to the complement regulator [[factor H]] from different animals.<ref name="pmid11796574">{{cite journal |author=Stevenson B, El-Hage N, Hines MA, Miller JC, and Babb K |title=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 |journal=Infect. Immun. |volume=70 |issue=2 |pages=491–497 |year=2002 |pmid=11796574 |doi=10.1128/IAI.70.2.491-497.2002 |pmc=127719}}</ref>  However, the presence of [[factor H]] was recently demonstrated to not be necessary to enable ''B. burgdorferi'' to infect mice, suggesting the Erp proteins have an additional function.<ref name="pmid17420242">{{cite journal |author=Woodman ME, Cooley AE, Miller JC, Lazarus JJ, Tucker K, Bykowski T, Botto M, Hellwage J, Wooten RM, and Stevenson B |title=''Borrelia burgdorferi'' binding of host complement regulator factor H is not required for efficient mammalian infection |journal=Infect. Immun. |volume=75 |issue=6 |pages=3131–3139 |year=2007 |pmid=17420242 |doi=10.1128/IAI.01923-06 |pmc=1932899}}</ref>
+OspE and OspF were initially identified in ''B. burgdorferi'' strain N40.<ref name="Lam 1994">{{cite journal |author=Lam TT, Nguyen TP, Montgomery RR, Kantor FS, Fikrig E, Flavell RA |title=Outer surface proteins E and F of ''Borrelia burgdorferi'', the agent of Lyme disease |journal=Infect. Immun. |volume=62 |issue=1 |pages=290–8 |year=1994 |pmid=8262642 |pmc=186099}}</ref>  The ''ospE'' and ''ospF'' genes are structurally arranged in tandem as one transcriptional unit under the control of a common promoter.<ref name="Lam 1994"/>  It is now known that individual strains of ''B. burgdorferi'' carry multiple related copies of the ''ospEF'' locus, which are now collectively referred to as ''erp'' (Osp''E''/F-like ''r''elated ''p''rotein).  In ''B. burgdoreri'' strains B31 and 297, most of the ''erp'' loci occupy the same position on the multiple copies of the cp32 plasmid present in these strains.<ref name="pmid11075913">{{cite journal |author=Stevenson B, Zückert WR, Akins DR |title=Repetition, conservation, and variation: the multiple cp32 plasmids of ''Borrelia'' species |journal=J. Mol. Microbiol. Biotechnol. |volume=2 |issue=4 |pages=411–422 |year=2000 |pmid=11075913 }}</ref>  Each ''erp'' locus consists of one or two ''erp'' genes.  When two genes are present, they are transcribed as one [[operon]], although in some cases, an internal promoter in the first gene may also transcribe the second gene.<ref name="pmid9596729">{{cite journal |author=Stevenson B, Bono JL, Schwan TG, Rosa P |title=''Borrelia burgdorferi'' Erp proteins are immunogenic in mammals infected by tick bite, and their synthesis is inducible in cultured bacteria |journal=Infect. Immun. |volume=66 |issue=6 |pages=2648–54 |year=1998 |pmid=9596729 |pmc=108251}}</ref>  The presence of multiple Erp proteins was proposed to be important in allowing ''B. burgdorferi'' to evade killing by the [[alternative complement pathway]] of a broad range of potential animal hosts, as individual Erp proteins exhibited different binding patterns to the complement regulator [[factor H]] from different animals.<ref name="pmid11796574">{{cite journal |author=Stevenson B, El-Hage N, Hines MA, Miller JC, Babb K |title=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 |journal=Infect. Immun. |volume=70 |issue=2 |pages=491–7 |year=2002 |pmid=11796574 |doi=10.1128/IAI.70.2.491-497.2002 |pmc=127719}}</ref>  However, the presence of [[factor H]] was recently demonstrated to not be necessary to enable ''B. burgdorferi'' to infect mice, suggesting the Erp proteins have an additional function.<ref name="pmid17420242">{{cite journal |author=Woodman ME, Cooley AE, Miller JC, Lazarus JJ, Tucker K, Bykowski T, Botto M, Hellwage J, Wooten RM, Stevenson B |title=''Borrelia burgdorferi'' binding of host complement regulator factor H is not required for efficient mammalian infection |journal=Infect. Immun. |volume=75 |issue=6 |pages=3131–9 |year=2007 |pmid=17420242 |doi=10.1128/IAI.01923-06 |pmc=1932899}}</ref>
 ==Mechanisms of persistence==
-While ''B.&nbsp;burgdorferi'' is susceptible to a number of [[antibiotics]] ''[[in vitro]]'', there are contradictory reports as to the efficacy of antibiotics ''[[in vivo]]''. ''B.&nbsp;burgdorferi'' may persist in humans and animals for months or years. Some studies have suggested persistence of infection despite antibiotic therapy,<ref name="Bayer">{{cite journal | author=Bayer ME and Zhang L, Bayer MH | title=''Borrelia burgdorferi'' DNA in the urine of treated patients with chronic Lyme disease symptoms. A PCR study of 97 cases | journal=Infection | year=1996 | pages=347–353 | volume=24 | issue=5 | pmid= 8923044 | doi=10.1007/BF01716077}}</ref><ref name="Preac-Mursic">{{cite journal | author=Preac-Mursic V | title=Survival of ''Borrelia burgdorferi'' in antibiotically treated patients with Lyme borreliosis | journal=Infection | year=1989 | pages=355–359 | volume=17 | issue=6 | pmid= 2613324 | doi=10.1007/BF01645543 | author-separator=, | author2=Weber K | author3=Pfister HW | display-authors=3 | last4=Weber | first4=K. | last5=Pfister | first5=H. W. | last6=Baumann | first6=A. | last7=Prokop | first7=J.}}</ref><ref name="Oksi-c">{{cite journal | author=Oksi J, Marjamaki M, Nikoskelainen J, and Viljanen MK | title=''Borrelia burgdorferi'' detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis | journal=Ann Med | year=1999 | pages=225–232 | volume=31 | issue=3 | pmid= 10442678 | doi=10.3109/07853899909115982}}</ref> although others suggested antibiotics rapidly end infections.<ref>{{cite journal |author=Nadelman RB |title=Failure to isolate Borrelia burgdorferi after antimicrobial therapy in culture-documented Lyme borreliosis associated with erythema migrans: report of a prospective study |journal=Am. J. Med. |volume=94 |issue=6 |pages=583–8 |year=1993 |month=June |pmid=8506882 |doi=10.1016/0002-9343(93)90208-7 |author-separator=, |author2=Nowakowski J |author3=Forseter G |display-authors=3 |last4=Bittker |first4=Susan |last5=Cooper |first5=Denise |last6=Goldberg |first6=Neil |last7=McKenna |first7=Donna |last8=Wormser |first8=Gary P.}}</ref><ref>{{cite journal |author=Muellegger RR |title=No detection of Borrelia burgdorferi-specific DNA in erythema migrans lesions after minocycline treatment |journal=Arch Dermatol |volume=131 |issue=6 |pages=678–82 |year=1995 |month=June |pmid=7778919 |doi=10.1001/archderm.131.6.678 |author-separator=, |author2=Zoechling N |author3=Soyer HP |display-authors=3 |last4=Hoedl |first4=S |last5=Wienecke |first5=R |last6=Volkenandt |first6=M |last7=Kerl |first7=H}}</ref>
+While ''B.&nbsp;burgdorferi'' is susceptible to a number of [[antibiotics]] ''[[in vitro]]'', there are contradictory reports as to the efficacy of antibiotics ''[[in vivo]]''. ''B.&nbsp;burgdorferi'' may persist in humans and animals for months or years. Some studies have suggested persistence of infection despite antibiotic therapy,<ref name="Bayer">{{cite journal | author=Bayer ME, Zhang L, Bayer MH | title=''Borrelia burgdorferi'' DNA in the urine of treated patients with chronic Lyme disease symptoms. A PCR study of 97 cases | journal=Infection | year=1996 | pages=347–353 | volume=24 | issue=5 | pmid= 8923044 | doi=10.1007/BF01716077}}</ref><ref name="Preac-Mursic">{{cite journal | author=Preac-Mursic V | title=Survival of ''Borrelia burgdorferi'' in antibiotically treated patients with Lyme borreliosis | journal=Infection | year=1989 | pages=355–9 | volume=17 | issue=6 | pmid= 2613324 | doi=10.1007/BF01645543 | author-separator=, | author2=Weber K | author3=Pfister HW | display-authors=3 | last4=Weber | first4=K. | last5=Pfister | first5=H. W. | last6=Baumann | first6=A. | last7=Prokop | first7=J.}}</ref><ref name="Oksi-c">{{cite journal | author=Oksi J, Marjamaki M, Nikoskelainen J, Viljanen MK | title=''Borrelia burgdorferi'' detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis | journal=Ann Med | year=1999 | pages=225–232 | volume=31 | issue=3 | pmid= 10442678 | doi=10.3109/07853899909115982}}</ref> although others suggested antibiotics rapidly end infections.<ref>{{cite journal |author=Nadelman RB |title=Failure to isolate ''Borrelia burgdorferi'' after antimicrobial therapy in culture-documented Lyme borreliosis associated with erythema migrans: report of a prospective study |journal=Am. J. Med. |volume=94 |issue=6 |pages=583–8 |year=1993 |month=June |pmid=8506882 |doi=10.1016/0002-9343(93)90208-7 |author-separator=, |author2=Nowakowski J |author3=Forseter G |display-authors=3 |last4=Bittker |first4=Susan |last5=Cooper |first5=Denise |last6=Goldberg |first6=Neil |last7=McKenna |first7=Donna |last8=Wormser |first8=Gary P.}}</ref><ref>{{cite journal |author=Muellegger RR |title=No detection of ''Borrelia burgdorferi''-specific DNA in erythema migrans lesions after minocycline treatment |journal=Arch Dermatol |volume=131 |issue=6 |pages=678–82 |year=1995 |month=June |pmid=7778919 |doi=10.1001/archderm.131.6.678 |author-separator=, |author2=Zoechling N |author3=Soyer HP |display-authors=3 |last4=Hoedl |first4=S |last5=Wienecke |first5=R |last6=Volkenandt |first6=M |last7=Kerl |first7=H}}</ref>
-Various survival strategies of ''B.&nbsp;burgdorferi'' have been posited to explain how the pathogen can persist in its host.<ref name="Embers">{{cite journal | author=Embers ME, Ramamoorthy R, and Philipp MT | title=Survival strategies of ''Borrelia burgdorferi'', the etiologic agent of Lyme disease | journal=Microbes Infect | year=2004 | pages=312–318 | volume=6 | issue=3 | pmid=15065567 | doi=10.1016/j.micinf.2003.11.014}}</ref> including the following:
+Various survival strategies of ''B.&nbsp;burgdorferi'' have been posited to explain how the pathogen can persist in its host.<ref name="Embers">{{cite journal | author=Embers ME, Ramamoorthy R, Philipp MT | title=Survival strategies of ''Borrelia burgdorferi'', the etiologic agent of Lyme disease | journal=Microbes Infect | year=2004 | pages=312–318 | volume=6 | issue=3 | pmid=15065567 | doi=10.1016/j.micinf.2003.11.014}}</ref> including the following:
-*Physical sequestration of ''B. burgdorferi'' in sites less accessible to the immune system and antibiotics, such as the [[brain]]<ref name="Miklossy">{{cite journal | author=Miklossy J | title=''Borrelia burgdorferi'' persists in the brain in chronic Lyme neuroborreliosis and may be associated with Alzheimer disease | journal=J Alzheimers Dis | year=2004 | pages=639–649; discussion 673–681 | volume=6 | issue=6 | pmid= 15665404 | author-separator=, | author2=Khalili K | author3=Gern L | display-authors=3 | last4=Ericson | first4=RL | last5=Darekar | first5=P | last6=Bolle | first6=L | last7=Hurlimann | first7=J | last8=Paster | first8=BJ}}</ref> and [[central nervous system]]. New evidence suggests that ''B.&nbsp;burgdorferi'' may use the host's [[fibrinolytic]] system to penetrate the [[blood–brain barrier]].<ref name="Grab">{{cite journal | author=Grab DJ, Perides G, Dumler JS, Kim KJ, Park J, Kim YV, Nikolskaia O, Choi KS, Stins MF, and Kim KS | title=''Borrelia burgdorferi'', host-derived proteases, and the blood–brain barrier | journal=Infect Immun | year=2005 | pages=1014–1022 | volume=73 | issue=2 | pmid= 15664945 | url=http://iai.asm.org/cgi/content/full/73/2/1014 | doi=10.1128/IAI.73.2.1014-1022.2005 | pmc=546937}}</ref>
+*Physical sequestration of ''B. burgdorferi'' in sites less accessible to the immune system and antibiotics, such as the [[brain]]<ref name="Miklossy">{{cite journal | author=Miklossy J | title=''Borrelia burgdorferi'' persists in the brain in chronic Lyme neuroborreliosis and may be associated with Alzheimer disease | journal=J Alzheimers Dis | year=2004 | pages=639–649; discussion 673–681 | volume=6 | issue=6 | pmid= 15665404 | author-separator=, | author2=Khalili K | author3=Gern L | display-authors=3 | last4=Ericson | first4=RL | last5=Darekar | first5=P | last6=Bolle | first6=L | last7=Hurlimann | first7=J | last8=Paster | first8=BJ}}</ref> and [[central nervous system]]. New evidence suggests that ''B.&nbsp;burgdorferi'' may use the host's [[fibrinolytic]] system to penetrate the [[blood–brain barrier]].<ref name="Grab">{{cite journal | author=Grab DJ, Perides G, Dumler JS, Kim KJ, Park J, Kim YV, Nikolskaia O, Choi KS, Stins MF, Kim KS | title=''Borrelia burgdorferi'', host-derived proteases, and the blood–brain barrier | journal=Infect Immun | year=2005 | pages=1014–1022 | volume=73 | issue=2 | pmid= 15664945 | url=http://iai.asm.org/cgi/content/full/73/2/1014 | doi=10.1128/IAI.73.2.1014-1022.2005 | pmc=546937}}</ref>
 *[[Intracellular]] invasion
-''B. burgdorferi'' can invade a variety of cultured cells, including [[endothelium]],<ref name="Ma-b">{{cite journal | author=Ma Y, Sturrock A, and Weis JJ | title=Intracellular localization of ''Borrelia burgdorferi'' within human endothelial cells | journal=Infect Immun | year=1991 | pages=671–678 | volume=59 | issue=2 | pmid= 1987083 | pmc=257809}}</ref> [[fibroblasts]],<ref name="Klempner-b">{{cite journal | author=Klempner MS, Noring R, and Rogers RA | title=Invasion of human skin fibroblasts by the Lyme disease spirochete, ''Borrelia burgdorferi'' | journal=J Infect Dis | year=1993 | pages=1074–1081 | volume=167 | issue=5 | pmid= 8486939 | doi=10.1093/infdis/167.5.1074}}</ref> [[lymphocytes]],<ref name="Dorward">{{cite journal | author=Dorward DW, Fischer ER, and Brooks DM | title=Invasion and cytopathic killing of human lymphocytes by spirochetes causing Lyme disease | journal=Clin Infect Dis | year=1997 | pages=S2–8 | volume=25 Suppl 1 | pmid= 9233657}}</ref> [[macrophages]],<ref name="Montgomery">{{cite journal | author=Montgomery RR, Nathanson MH, and Malawista SE | title=The fate of ''Borrelia burgdorferi'', the agent for Lyme disease, in mouse macrophages. Destruction, survival, recovery | journal=J Immunol | year=1993 | pages=909–915 | volume=150 | issue=3 | pmid= 8423346}}</ref> [[keratinocytes]],<ref name="Aberer">{{cite journal | author=Aberer E, Kersten A, Klade H, Poitschek C, and Jurecka W | title=Heterogeneity of ''Borrelia burgdorferi'' in the skin | journal=Neurosci Lett. | year=1996 | pages=112–116 | date=2005 August 12–19 | volume=384 | issue=1–2 | pmid=15893422 | doi=10.1016/j.neulet.2005.04.069}}</ref> [[synovium]],<ref name="Girschick">{{cite journal | author=Girschick HJ, Huppertz HI, Russmann H, Krenn V, and Karch H | title=Intracellular persistence of ''Borrelia burgdorferi'' in human synovial cells | journal=Rheumatol Int | year=1996 | pages=125–132 | volume=16 | issue=3 | pmid= 8893378 | doi=10.1007/BF01409985}}</ref><ref name="Nanagara">{{cite journal | author=Nanagara R, Duray PH, and Schumacher HR Jr | title=Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic Lyme disease: possible factors contributing to persistence of organisms | journal=Hum Pathol | year=1996 | pages=1025–1034 | volume=27 | issue=10 | pmid= 8892586 | doi=10.1016/S0046-8177(96)90279-8}}</ref> and most recently [[neuronal]] and [[glial cells]].<ref name="Livengood">{{cite journal | author=Livengood JA, Gilmore RD | title = Invasion of human neuronal and glial cells by an infectious strain of ''Borrelia burgdorferi'' | journal = Microbes Infect | volume = [Epub ahead of print] | year=2006 | pmid=17045505 | issue=14–15 | pages=2832–40 | doi=10.1016/j.micinf.2006.08.014}}</ref> By 'hiding' inside these cells during human infection, ''B.&nbsp;burgdorferi'' may be able to evade the immune system and be protected to varying degrees against some antibiotics,<ref name="Georgilis">{{cite journal | author=Georgilis K, Peacocke M, Klempner MS | title=Fibroblasts protect the Lyme disease spirochete, ''Borrelia burgdorferi'', from ceftriaxone ''in vitro'' | journal=J Infect Dis | year=1992 | pages=440–444 | volume=166 | issue=2 | pmid= 1634816 | doi=10.1093/infdis/166.2.440}}</ref><ref name="Brouqui">{{cite journal | author=Brouqui P, Badiaga S, and Raoult D | title=Eucaryotic cells protect ''Borrelia burgdorferi'' from the action of penicillin and ceftriaxone but not from the action of doxycycline and erythromycin | journal=Antimicrob Agents Chemother | year=1996 | pages=1552–1554 | volume=40 | issue=6 | pmid= 8726038 | url=http://aac.asm.org/cgi/reprint/40/6/1552.pdf | format=PDF | pmc=163368}}</ref> sometimes allowing the infection to persist.  However it remains unknown whether the ''in vitro'' observations made with cultured cells are relevant to persistent infection in Lyme disease patients as there have been few reports of intracellular ''B. burgdorferi'' ''in vivo''.<ref name="Embers"/>
+''B. burgdorferi'' can invade a variety of cultured cells, including [[endothelium]],<ref name="Ma-b">{{cite journal | author=Ma Y, Sturrock A, Weis JJ | title=Intracellular localization of ''Borrelia burgdorferi'' within human endothelial cells | journal=Infect Immun | year=1991 | pages=671–678 | volume=59 | issue=2 | pmid= 1987083 | pmc=257809}}</ref> [[fibroblasts]],<ref name="Klempner-b">{{cite journal | author=Klempner MS, Noring R, Rogers RA | title=Invasion of human skin fibroblasts by the Lyme disease spirochete, ''Borrelia burgdorferi'' | journal=J Infect Dis | year=1993 | pages=1074–1081 | volume=167 | issue=5 | pmid= 8486939 | doi=10.1093/infdis/167.5.1074}}</ref> [[lymphocytes]],<ref name="Dorward">{{cite journal | author=Dorward DW, Fischer ER, Brooks DM | title=Invasion and cytopathic killing of human lymphocytes by spirochetes causing Lyme disease | journal=Clin Infect Dis | year=1997 | pages=S2–8 | volume=25 |issue=Suppl 1 | pmid= 9233657}}</ref> [[macrophages]],<ref name="Montgomery">{{cite journal | author=Montgomery RR, Nathanson MH, Malawista SE | title=The fate of ''Borrelia burgdorferi'', the agent for Lyme disease, in mouse macrophages. Destruction, survival, recovery | journal=J Immunol | year=1993 | pages=909–915 | volume=150 | issue=3 | pmid= 8423346}}</ref> [[keratinocytes]],<ref name="Aberer">{{cite journal | author=Aberer E, Kersten A, Klade H, Poitschek C, Jurecka W | title=Heterogeneity of ''Borrelia burgdorferi'' in the skin | journal=Neurosci Lett. | year=1996 | pages=112–116 | date=2005 August 12–19 | volume=384 | issue=1–2 | pmid=15893422 | doi=10.1016/j.neulet.2005.04.069}}</ref> [[synovium]],<ref name="Girschick">{{cite journal | author=Girschick HJ, Huppertz HI, Russmann H, Krenn V, Karch H | title=Intracellular persistence of ''Borrelia burgdorferi'' in human synovial cells | journal=Rheumatol Int | year=1996 | pages=125–132 | volume=16 | issue=3 | pmid= 8893378 | doi=10.1007/BF01409985}}</ref><ref name="Nanagara">{{cite journal | author=Nanagara R, Duray PH, Schumacher HR Jr | title=Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic Lyme disease: possible factors contributing to persistence of organisms | journal=Hum Pathol | year=1996 | pages=1025–1034 | volume=27 | issue=10 | pmid= 8892586 | doi=10.1016/S0046-8177(96)90279-8}}</ref> and most recently [[neuronal]] and [[glial cells]].<ref name="Livengood">{{cite journal | author=Livengood JA, Gilmore RD | title = Invasion of human neuronal and glial cells by an infectious strain of ''Borrelia burgdorferi'' | journal = Microbes Infect | volume = 8 | year=2006 | pmid=17045505 | issue=14–15 | pages=2832–40 | doi=10.1016/j.micinf.2006.08.014}}</ref> By 'hiding' inside these cells during human infection, ''B.&nbsp;burgdorferi'' may be able to evade the immune system and be protected to varying degrees against some antibiotics,<ref name="Georgilis">{{cite journal | author=Georgilis K, Peacocke M, Klempner MS | title=Fibroblasts protect the Lyme disease spirochete, ''Borrelia burgdorferi'', from ceftriaxone ''in vitro'' | journal=J Infect Dis | year=1992 | pages=440–444 | volume=166 | issue=2 | pmid= 1634816 | doi=10.1093/infdis/166.2.440}}</ref><ref name="Brouqui">{{cite journal | author=Brouqui P, Badiaga S, Raoult D | title=Eucaryotic cells protect ''Borrelia burgdorferi'' from the action of penicillin and ceftriaxone but not from the action of doxycycline and erythromycin | journal=Antimicrob Agents Chemother | year=1996 | pages=1552–1554 | volume=40 | issue=6 | pmid= 8726038 | url=http://aac.asm.org/cgi/reprint/40/6/1552.pdf | format=PDF | pmc=163368}}</ref> sometimes allowing the infection to persist.  However it remains unknown whether the ''in vitro'' observations made with cultured cells are relevant to persistent infection in Lyme disease patients as there have been few reports of intracellular ''B. burgdorferi'' ''in vivo''.<ref name="Embers"/>
 *Altered [[morphology (biology)|morphological]] [[forms]], i.e. round bodies (cysts, granules, [[spheroplast]]s)
-The formation of rounded forms of ''B.&nbsp;burgdorferi'' cells, sometimes called ''spheroplasts'', which either lack a [[cell wall]] or have a damaged cell wall, has been observed ''in vitro'',<ref name="Alban">{{cite journal | author=Alban PS, Johnson PW, and Nelson DR | title=Serum-starvation-induced changes in protein synthesis and morphology of ''Borrelia burgdorferi'' | journal=Microbiology | date=1 January 2000| pages=119–127 | volume=146 | pmid= 10658658 | url =http://mic.sgmjournals.org/cgi/content/full/146/1/119 | issue=1 }}</ref><ref name="Mursic">{{cite journal | author=Mursic VP | title=Formation and cultivation of ''Borrelia burgdorferi'' spheroplast-L-form variants | journal=Infection | year=1996 | pages=218–226 | volume=24 | issue=3 | pmid= 8811359 | doi=10.1007/BF01781096 | author-separator=, | author2=Wanner G | author3=Reinhardt S | display-authors=3 | last4=Busch | first4=U. | last5=Wanner | first5=G. | last6=Marget | first6=W.}}</ref><ref name="Kersten">{{cite journal | author=Kersten A, Poitschek C, Rauch S, and Aberer E | title=Effects of penicillin, ceftriaxone, and doxycycline on morphology of ''Borrelia burgdorferi'' | journal=Antimicrob Agents Chemother | year=1995 | pages=1127–1133 | volume=39 | issue=5 | pmid= 7625800 | url=http://aac.asm.org/cgi/reprint/39/5/1127.pdf | format=PDF | pmc=162695}}</ref><ref name="Schaller">{{cite journal | author=Schaller M, Neubert U | title=Ultrastructure of ''Borrelia burgdorferi'' after exposure to benzylpenicillin | journal=Infection | year=1994 | pages=401–406 | volume=22 | issue=6 | pmid= 7698837 | doi=10.1007/BF01715497}}</ref> [[in vivo]],<ref name="Nanagara" /><ref name="Phillips-c">{{cite journal | author=Phillips SE, Mattman LH, Hulinska D, and Moayad H | title=A proposal for the reliable culture of ''Borrelia burgdorferi'' from patients with chronic Lyme disease, even from those previously aggressively treated | journal=Infection | year=1998 | pages=364–367 | volume=26 | issue=6 | pmid= 9861561 | url=http://www.cbc.ca/ideas/features/Aids/phillips.html | doi=10.1007/BF02770837}}</ref> and in an [[ex vivo]] model.<ref name="Duray">{{cite journal | author=Duray PH | title=Invasion of human tissue ex vivo by ''Borrelia burgdorferi'' | journal=J Infect Dis | year=2005 | pages=1747–1754 | volume=191 | issue=10 | pmid= 15838803 | doi=10.1086/429632 | author-separator=, | author2=Yin SR | author3=Ito Y | display-authors=3 | last4=Bezrukov | first4=Ludmila | last5=Cox | first5=Cheri | last6=Cho | first6=Myong‐Soon | last7=Fitzgerald | first7=Wendy | last8=Dorward | first8=David | last9=Zimmerberg | first9=Joshua}}</ref> The finding that energy is required for the spiral bacterium to convert to this form<ref name="Alban" /> suggests that these altered forms have a survival function, and are not merely end stage degeneration products. Some data suggest these rounded cells are [[virulent]] and [[infection|infectious]], are able to survive under adverse environmental conditions, and may revert to the spiral form ''in vitro'', once conditions are more favorable.<ref name="Gruntar">{{cite journal | author=Gruntar I, Malovrh T, Murgia R, and Cinco M | title=Conversion of ''Borrelia garinii'' cystic forms to motile spirochetes ''in vivo'' | journal=APMIS | year=2001 | pages=383–388 | volume=109 | issue=5 | pmid= 11478686 | doi=10.1034/j.1600-0463.2001.090507.x}}</ref><ref name="Murgia">{{cite journal | author=Murgia R and Cinco M | title=Induction of cystic forms by different stress conditions in ''Borrelia burgdorferi'' | journal=APMIS | year=2004 | pages=57–62 | volume=112 | issue=1 | pmid= 14961976 | doi=10.1111/j.1600-0463.2004.apm1120110.x}}</ref> However, rounded cell types triggered by an antibody binding to the OspB surface protein are damaged and dying forms of the bacteria and do not represent a separate form of the organism.<ref>{{cite journal |author=Escudero R, Halluska ML, Backenson PB, Coleman JL, Benach JL |title=Characterization of the physiological requirements for the bactericidal effects of a monoclonal antibody to OspB of Borrelia burgdorferi by confocal microscopy |journal=Infect. Immun. |volume=65 |issue=5 |pages=1908–15 |date=1 May 1997|pmid=9125579 |pmc=175240 |url=http://iai.asm.org/cgi/pmidlookup?view=long&pmid=9125579 }}</ref>
+The formation of rounded forms of ''B.&nbsp;burgdorferi'' cells, sometimes called ''spheroplasts'', which either lack a [[cell wall]] or have a damaged cell wall, has been observed ''in vitro'',<ref name="Alban">{{cite journal | author=Alban PS, Johnson PW, Nelson DR | title=Serum-starvation-induced changes in protein synthesis and morphology of ''Borrelia burgdorferi'' | journal=Microbiology | date=1 January 2000| pages=119–127 | volume=146 | pmid= 10658658 | url =http://mic.sgmjournals.org/cgi/content/full/146/1/119 | issue=1 }}</ref><ref name="Mursic">{{cite journal | author=Mursic VP | title=Formation and cultivation of ''Borrelia burgdorferi'' spheroplast-L-form variants | journal=Infection | year=1996 | pages=218–226 | volume=24 | issue=3 | pmid= 8811359 | doi=10.1007/BF01781096 | author-separator=, | author2=Wanner G | author3=Reinhardt S | display-authors=3 | last4=Busch | first4=U. | last5=Wanner | first5=G. | last6=Marget | first6=W.}}</ref><ref name="Kersten">{{cite journal | author=Kersten A, Poitschek C, Rauch S, Aberer E | title=Effects of penicillin, ceftriaxone, and doxycycline on morphology of ''Borrelia burgdorferi'' | journal=Antimicrob Agents Chemother | year=1995 | pages=1127–1133 | volume=39 | issue=5 | pmid= 7625800 | url=http://aac.asm.org/cgi/reprint/39/5/1127.pdf | format=PDF | pmc=162695}}</ref><ref name="Schaller">{{cite journal | author=Schaller M, Neubert U | title=Ultrastructure of ''Borrelia burgdorferi'' after exposure to benzylpenicillin | journal=Infection | year=1994 | pages=401–406 | volume=22 | issue=6 | pmid= 7698837 | doi=10.1007/BF01715497}}</ref> [[in vivo]],<ref name="Nanagara" /><ref name="Phillips-c">{{cite journal | author=Phillips SE, Mattman LH, Hulinska D, Moayad H | title=A proposal for the reliable culture of ''Borrelia burgdorferi'' from patients with chronic Lyme disease, even from those previously aggressively treated | journal=Infection | year=1998 | pages=364–367 | volume=26 | issue=6 | pmid= 9861561 | url=http://www.cbc.ca/ideas/features/Aids/phillips.html | doi=10.1007/BF02770837}}</ref> and in an [[ex vivo]] model.<ref name="Duray">{{cite journal | author=Duray PH | title=Invasion of human tissue ex vivo by ''Borrelia burgdorferi'' | journal=J Infect Dis | year=2005 | pages=1747–1754 | volume=191 | issue=10 | pmid= 15838803 | doi=10.1086/429632 | author-separator=, | author2=Yin SR | author3=Ito Y | display-authors=3 | last4=Bezrukov | first4=Ludmila | last5=Cox | first5=Cheri | last6=Cho | first6=Myong‐Soon | last7=Fitzgerald | first7=Wendy | last8=Dorward | first8=David | last9=Zimmerberg | first9=Joshua}}</ref> The finding that energy is required for the spiral bacterium to convert to this form<ref name="Alban" /> suggests that these altered forms have a survival function, and are not merely end stage degeneration products. Some data suggest these rounded cells are [[virulent]] and [[infection|infectious]], are able to survive under adverse environmental conditions, and may revert to the spiral form ''in vitro'', once conditions are more favorable.<ref name="Gruntar">{{cite journal | author=Gruntar I, Malovrh T, Murgia R, Cinco M | title=Conversion of ''Borrelia garinii'' cystic forms to motile spirochetes ''in vivo'' | journal=APMIS | year=2001 | pages=383–388 | volume=109 | issue=5 | pmid= 11478686 | doi=10.1034/j.1600-0463.2001.090507.x}}</ref><ref name="Murgia">{{cite journal | author=Murgia R, Cinco M | title=Induction of cystic forms by different stress conditions in ''Borrelia burgdorferi'' | journal=APMIS | year=2004 | pages=57–62 | volume=112 | issue=1 | pmid= 14961976 | doi=10.1111/j.1600-0463.2004.apm1120110.x}}</ref> However, rounded cell types triggered by an antibody binding to the OspB surface protein are damaged and dying forms of the bacteria and do not represent a separate form of the organism.<ref>{{cite journal |author=Escudero R, Halluska ML, Backenson PB, Coleman JL, Benach JL |title=Characterization of the physiological requirements for the bactericidal effects of a monoclonal antibody to OspB of ''Borrelia burgdorferi'' by confocal microscopy |journal=Infect. Immun. |volume=65 |issue=5 |pages=1908–15 |date=1 May 1997|pmid=9125579 |pmc=175240 |url=http://iai.asm.org/cgi/pmidlookup?view=long&pmid=9125579 }}</ref>
-Compared to the spiral form, spheroplasts of ''B. burgdorferi'' have reduced surface area exposed to immune surveillance.{{Citation needed|date=November 2008}} They also express some different surface proteins from spirochetes. ''B.&nbsp;burgdorferi'' spheroplasts have shown sensitivity ''in vitro'' to [[Human parasitic diseases|antiparasitic]] drugs, such as [[metronidazole]],<ref name="Brorson-c">{{cite journal | author=Brorson O and Brorson SH | title=An ''in vitro'' study of the susceptibility of mobile and cystic forms of ''Borrelia burgdorferi'' to metronidazole | journal=APMIS | year=1999 | pages=566–576 | volume=107 | issue=6 | pmid= 10379684 | doi=10.1111/j.1699-0463.1999.tb01594.x}}</ref> [[tinidazole]],<ref name="Brorson-d">{{cite journal | author=Brorson O and Brorson SH | title=An ''in vitro'' study of the susceptibility of mobile and cystic forms of ''Borrelia burgdorferi'' to tinidazole | journal=Int Microbiol | year=2004 | pages=139–142 | volume=7 | issue=2 | pmid= 15248163 | url=http://www.im.microbios.org/26June04/09%20Brorson.pdf | format=PDF}}</ref> and [[hydroxychloroquine]]&nbsp;<ref name="Brorson-e">{{cite journal | author=Brorson O and Brorson SH | title=An ''in vitro'' study of the susceptibility of mobile and cystic forms of ''Borrelia burgdorferi'' to hydroxychloroquine | journal=Int Microbiol | year=2002 | pages=25–31 | volume=5 | issue=1 | pmid= 12102233 | doi=10.1007/s10123-002-0055-2}}</ref> to which the spiral form of ''B.&nbsp;burgdorferi'' is not sensitive.
+Compared to the spiral form, spheroplasts of ''B. burgdorferi'' have reduced surface area exposed to immune surveillance.{{Citation needed|date=November 2008}} They also express some different surface proteins from spirochetes. ''B.&nbsp;burgdorferi'' spheroplasts have shown sensitivity ''in vitro'' to [[Human parasitic diseases|antiparasitic]] drugs, such as [[metronidazole]],<ref name="Brorson-c">{{cite journal | author=Brorson O, Brorson SH | title=An ''in vitro'' study of the susceptibility of mobile and cystic forms of ''Borrelia burgdorferi'' to metronidazole | journal=APMIS | year=1999 | pages=566–576 | volume=107 | issue=6 | pmid= 10379684 | doi=10.1111/j.1699-0463.1999.tb01594.x}}</ref> [[tinidazole]],<ref name="Brorson-d">{{cite journal | author=Brorson O, Brorson SH | title=An ''in vitro'' study of the susceptibility of mobile and cystic forms of ''Borrelia burgdorferi'' to tinidazole | journal=Int Microbiol | year=2004 | pages=139–142 | volume=7 | issue=2 | pmid= 15248163 | url=http://www.im.microbios.org/26June04/09%20Brorson.pdf | format=PDF}}</ref> and [[hydroxychloroquine]]&nbsp;<ref name="Brorson-e">{{cite journal | author=Brorson O, Brorson SH | title=An ''in vitro'' study of the susceptibility of mobile and cystic forms of ''Borrelia burgdorferi'' to hydroxychloroquine | journal=Int Microbiol | year=2002 | pages=25–31 | volume=5 | issue=1 | pmid= 12102233 | doi=10.1007/s10123-002-0055-2}}</ref> to which the spiral form of ''B.&nbsp;burgdorferi'' is not sensitive.
 *[[Antigen]]ic variation and [[gene expression]]
@@ Line 120: / Line 120: @@
 *[[Immune system]] suppression.
-[[Complement system|Complement]] inhibition, induction of anti-inflammatory [[cytokines]] such as [[Interleukin 10|IL-10]], and the formation of [[immune complex]]es have all been documented in ''B.&nbsp;burgdorferi'' infection.<ref name="Embers" /> Furthermore, the existence of immune complexes may be involved in [[seronegative]] acute-phase disease (i.e. [[Type I and type II errors|false-negative]] antibody tests of [[blood]] and [[cerebrospinal fluid]]). One study shows some acute-phase seronegative Lyme patients have antibodies bound up in these complexes.<ref name="Schutzer">{{cite journal | author=Schutzer SE, Coyle PK, Reid P, and Holland B | title=''Borrelia burgdorferi''-specific immune complexes in acute Lyme disease | journal=JAMA | year=1999 | pages=1942–1946 | volume=282 | issue=20 | pmid= 10580460 | doi=10.1001/jama.282.20.1942}}</ref>
+[[Complement system|Complement]] inhibition, induction of anti-inflammatory [[cytokines]] such as [[Interleukin 10|IL-10]], and the formation of [[immune complex]]es have all been documented in ''B.&nbsp;burgdorferi'' infection.<ref name="Embers" /> Furthermore, the existence of immune complexes may be involved in [[seronegative]] acute-phase disease (i.e. [[Type I and type II errors|false-negative]] antibody tests of [[blood]] and [[cerebrospinal fluid]]). One study shows some acute-phase seronegative Lyme patients have antibodies bound up in these complexes.<ref name="Schutzer">{{cite journal | author=Schutzer SE, Coyle PK, Reid P, Holland B | title=''Borrelia burgdorferi''-specific immune complexes in acute Lyme disease | journal=JAMA | year=1999 | pages=1942–1946 | volume=282 | issue=20 | pmid= 10580460 | doi=10.1001/jama.282.20.1942}}</ref>
 ==Advancing immunology research==
@@ Line 126: / Line 126: @@
 {{Further| Lyme Disease#Advancing Immunology Research}}
-The role of [[T cells]] in ''Borrelia'' was first made in 1984,<ref>{{cite journal | author=Newman K Jr and Johnson RC | title=T-cell-independent elimination of ''Borrelia turicatae'' | journal=Infect Immun. | year=1984 |month=September | volume=45 | issue=3 | pages=572–576 | pmid=6332075 | pmc=263332}}</ref> the role of cellular immunity in active Lyme disease was made in 1986,<ref>{{cite journal |coauthors=Dattwyler RJ, Thomas JA, Benach JL, and Golightly MG | title=Cellular immune response in Lyme disease: the response to mitogens, live ''Borrelia burgdorferi'', NK cell function and lymphocyte subsets | journal=Zentralbl Bakteriol Mikrobiol Hyg [A] | year=1986 | month=Dec | volume=263 | issue=1–2 | pages=151–159}}</ref> and long term persistence of T cell [[lymphocyte]] responses to ''B.&nbsp;burgdorferi'' as an "immunological scar syndrome" was hypothesized in 1990.<ref>{{cite journal | author=Kruger H, Pulz M, Martin R, and Sticht-Groh V | title=Long-term persistence of specific T- and B-lymphocyte responses to ''Borrelia burgdorferi'' following untreated neuroborreliosis | journal=Infection | year=1990 | month=Sep-Oct | volume=18 | issue=5 | pages=263–267 | doi=10.1007/BF01646998 | pmid=2276818}}</ref> The role of [[Th1 cell|Th1]] and [[interferon-gamma]] (IFN-gamma) in ''Borrelia'' was first described in 1995.<ref>{{cite journal | doi=10.1111/j.1365-2249.1995.tb03134.x | author=Forsberg P, Ernerudh J, Ekerfelt C, Roberg M, Vrethem M, and Bergstrom S | title=The outer surface proteins of Lyme disease ''Borrelia'' spirochetes stimulate T cells to secrete interferon-gamma (IFN-gamma): diagnostic and pathogenic implications | journal=Clin Exp Immunol. | year=1995 | month=September | volume=101 | issue=3 | pages=453–460 | pmid=7664493 | pmc=1553228}}</ref> The [[cytokine]] pattern of Lyme disease, and the role of Th1 with down regulation of [[interleukin-10]] (IL-10) was first proposed in 1997.<ref>{{cite journal | author=Yin Z, Braun J, Neure L, Wu P, Eggens U, Krause A, Kamradt T, and Sieper J | title=T cell cytokine pattern in the joints of patients with Lyme arthritis and its regulation by cytokines and anticytokines | journal=Arthritis Rheum. | year=1997 | month=January | volume=40 | issue=1 | pages=69–79 | doi=10.1002/art.1780400111 | pmid=9008602}}</ref>
+The role of [[T cells]] in ''Borrelia'' was first made in 1984,<ref>{{cite journal | author=Newman K Jr and Johnson RC | title=T-cell-independent elimination of ''Borrelia turicatae'' | journal=Infect Immun. | year=1984 |month=September | volume=45 | issue=3 | pages=572–576 | pmid=6332075 | pmc=263332}}</ref> the role of cellular immunity in active Lyme disease was made in 1986,<ref>{{cite journal |coauthors=Dattwyler RJ, Thomas JA, Benach JL, Golightly MG | title=Cellular immune response in Lyme disease: the response to mitogens, live ''Borrelia burgdorferi'', NK cell function and lymphocyte subsets | journal=Zentralbl Bakteriol Mikrobiol Hyg [A] | year=1986 | month=Dec | volume=263 | issue=1–2 | pages=151–159}}</ref> and long term persistence of T cell [[lymphocyte]] responses to ''B.&nbsp;burgdorferi'' as an "immunological scar syndrome" was hypothesized in 1990.<ref>{{cite journal | author=Kruger H, Pulz M, Martin R, Sticht-Groh V | title=Long-term persistence of specific T- and B-lymphocyte responses to ''Borrelia burgdorferi'' following untreated neuroborreliosis | journal=Infection | year=1990 | month=Sep-Oct | volume=18 | issue=5 | pages=263–267 | doi=10.1007/BF01646998 | pmid=2276818}}</ref> The role of [[Th1 cell|Th1]] and [[interferon-gamma]] (IFN-gamma) in ''Borrelia'' was first described in 1995.<ref>{{cite journal | doi=10.1111/j.1365-2249.1995.tb03134.x | author=Forsberg P, Ernerudh J, Ekerfelt C, Roberg M, Vrethem M, Bergstrom S | title=The outer surface proteins of Lyme disease ''Borrelia'' spirochetes stimulate T cells to secrete interferon-gamma (IFN-gamma): diagnostic and pathogenic implications | journal=Clin Exp Immunol. | year=1995 | month=September | volume=101 | issue=3 | pages=453–460 | pmid=7664493 | pmc=1553228}}</ref> The [[cytokine]] pattern of Lyme disease, and the role of Th1 with down regulation of [[interleukin-10]] (IL-10) was first proposed in 1997.<ref>{{cite journal | author=Yin Z, Braun J, Neure L, Wu P, Eggens U, Krause A, Kamradt T, Sieper J | title=T cell cytokine pattern in the joints of patients with Lyme arthritis and its regulation by cytokines and anticytokines | journal=Arthritis Rheum. | year=1997 | month=January | volume=40 | issue=1 | pages=69–79 | doi=10.1002/art.1780400111 | pmid=9008602}}</ref>
 Recent studies in both acute and antibiotic refractory, or chronic, Lyme disease have shown a distinct [[inflammation|pro-inflammatory]] immune process. This pro-inflammatory process is a [[cell-mediated immunity]] and results in Th1 upregulation. These studies have shown a significant decrease in [[cytokine]] output of (IL-10), an upregulation of [[interleukin-6]] (IL-6) and [[interleukin-12]] (Il-12) and [[interferon-gamma]] (IFN-gamma) and dysregulation in [[TNF-alpha]],` predominantly.
-New research has also found chronic Lyme patients have higher amounts of ''Borrelia''-specific [[FoxP3|forkhead box P3]] (FoxP3) than healthy controls, indicating [[regulatory T cell]]s might also play a role, by [[immunosuppression]], in the development of chronic Lyme disease. FoxP3 are a specific marker of regulatory T cells.<ref>{{cite journal | author=Jarefors S, Janefjord CK, Forsberg P, Jenmalm MC, and Ekerfelt C | title=Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic ''Borrelia''-exposed individuals | journal=Clin Exp Immunol. | year=2007 | month=January | volume=147 | issue=1 | pages=18–27 | pmid=17177959 | doi=10.1111/j.1365-2249.2006.03245.x | pmc=1810439}}</ref> The signaling pathway [[P38 mitogen-activated protein kinases]] (p38 MAP kinase) has also been identified as promoting expression of proinflammatory cytokines from borrelia.<ref>{{cite journal | author=Olson CM, Hedrick MN, Izadi H, Bates TC, Olivera ER, and Anguita J | title=p38 mitogen-activated protein kinase controls NF-kappaB transcriptional activation and tumor necrosis factor alpha production through RelA phosphorylation mediated by mitogen- and stress-activated protein kinase 1 in response to ''Borrelia burgdorferi'' antigens | journal=Infect Immun. | year=2007 | month=January | volume=75 | issue=1 | pages=270–277 | date=2006-10-30 | pmid=17074860 | doi=10.1128/IAI.01412-06 | pmc=1828394}}</ref><ref>{{cite journal | author=Ramesh G and Philipp MT | title=Pathogenesis of Lyme neuroborreliosis: mitogen-activated protein kinases Erk1, Erk2, and p38 in the response of astrocytes to ''Borrelia burgdorferi'' lipoproteins | journal=Neurosci Lett. | date=2005 August 12–19 | volume=384 | issue=1–2 | pages=112–116 | doi=10.1016/j.neulet.2005.04.069 | pmid=15893422}}</ref>
+New research has also found chronic Lyme patients have higher amounts of ''Borrelia''-specific [[FoxP3|forkhead box P3]] (FoxP3) than healthy controls, indicating [[regulatory T cell]]s might also play a role, by [[immunosuppression]], in the development of chronic Lyme disease. FoxP3 are a specific marker of regulatory T cells.<ref>{{cite journal | author=Jarefors S, Janefjord CK, Forsberg P, Jenmalm MC, Ekerfelt C | title=Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic ''Borrelia''-exposed individuals | journal=Clin Exp Immunol. | year=2007 | month=January | volume=147 | issue=1 | pages=18–27 | pmid=17177959 | doi=10.1111/j.1365-2249.2006.03245.x | pmc=1810439}}</ref> The signaling pathway [[P38 mitogen-activated protein kinases]] (p38 MAP kinase) has also been identified as promoting expression of proinflammatory cytokines from borrelia.<ref>{{cite journal | author=Olson CM, Hedrick MN, Izadi H, Bates TC, Olivera ER, Anguita J | title=p38 mitogen-activated protein kinase controls NF-kappaB transcriptional activation and tumor necrosis factor alpha production through RelA phosphorylation mediated by mitogen- and stress-activated protein kinase 1 in response to ''Borrelia burgdorferi'' antigens | journal=Infect Immun. | year=2007 | month=January | volume=75 | issue=1 | pages=270–277 | date=2006-10-30 | pmid=17074860 | doi=10.1128/IAI.01412-06 | pmc=1828394}}</ref><ref>{{cite journal | author=Ramesh G, Philipp MT | title=Pathogenesis of Lyme neuroborreliosis: mitogen-activated protein kinases Erk1, Erk2, and p38 in the response of astrocytes to ''Borrelia burgdorferi'' lipoproteins | journal=Neurosci Lett. | date=2005 August 12–19 | volume=384 | issue=1–2 | pages=112–116 | doi=10.1016/j.neulet.2005.04.069 | pmid=15893422}}</ref>
 The culmination of these new and ongoing immunological studies suggest this cell-mediated immune disruption in the Lyme patient amplifies the inflammatory process, often rendering it chronic and self-perpetuating, regardless of whether the ''Borrelia'' bacterium is still present in the host, or in the absence of the inciting pathogen in an [[autoimmune]] pattern.<ref>{{cite journal |author=Singh SK, Girschick HJ |title=Toll-like receptors in ''Borrelia burgdorferi''-induced inflammation |journal=Clin. Microbiol. Infect. |volume=12 |issue=8 |pages=705–17 |year=2006 |pmid=16842565 |doi=10.1111/j.1469-0691.2006.01440.x}}</ref>
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 Due to its universal and high level expression, outer surface protein A (OspA) was the natural focus of early vaccine development efforts.  An OspA-based vaccine (LYMErix; [[SmithKline Beecham]]) was licensed for use in adults.  However, this vaccine was voluntarily removed from the market by its manufacturer in 2002.  Recently, considerable progress in the development of broadly protective Lyme disease vaccines has been made.  In particular, there is a focus on alternative vaccine candidates that may require fewer boosts and will conceivably provide long term protection. There is interest in developing vaccines that specifically target the tick vectors of Lyme disease, specifically components of tick saliva that coat the bacteria. This approach offers the advantage of protecting against multiple pathogens with one vaccine.<ref>"Tick saliva." The Science Teacher 77.1 (2010): 14.</ref>  While an effective Lyme disease vaccine seems likely to be developed, earlier experiences with the LYMErix vaccine suggest that bringing such a vaccine to market will be a challenge.<ref name= Marconi2010>{{cite book |author= Marconi, RT; Earnhart, CG| year=2010 |chapter=Lyme Disease Vaccines|title=''Borrelia'': Molecular Biology, Host Interaction and Pathogenesis | publisher=Caister Academic Press | isbn= 978-1-904455-58-5}}</ref>
-A vaccine made by [[Pfizer]] known as LymeVax is currently available for use in dogs. Having dogs vaccinated should also help to protect their owners from infection by the dog. The vaccine is a 2-strain, multi-antigen vaccime which induces an antibody response to bacterial proteins OspA and OspC.<ref name= LymeVax>{{cite web |url= https://animalhealth.pfizer.com/sites/pahweb/US/EN/Products/Pages/LymeVax.aspx |title= LymeVax |author= |date= |work= Product page |publisher= Pfizer |accessdate=11 April 2012}}</ref>
+A vaccine made by [[Pfizer]] known as LymeVax is currently available for use in dogs. Having dogs vaccinated should also help to protect their owners from infection by the dog. The vaccine is a 2-strain, multi-antigen vaccime which induces an antibody response to bacterial proteins OspA and OspC.<ref name= LymeVax>{{cite web |url= https://animalhealth.pfizer.com/sites/pahweb/US/EN/Products/Pages/LymeVax.aspx |title= LymeVax |work= Product page |publisher= Pfizer |accessdate=11 April 2012}}</ref>
 ==References==
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 *[http://cmr.jcvi.org/tigr-scripts/CMR/GenomePage.cgi?org=ntbg01 ''Borrelia garinii'' PBi Genome Page]
 *[http://cmr.jcvi.org/tigr-scripts/CMR/GenomePage.cgi?org=ntba07 ''Borrelia afzelli'' PKo Genome Page]
+*{{cite journal |author=Schwan TG, Piesman J |title=Vector interactions and molecular adaptations of lyme disease and relapsing fever spirochetes associated with transmission by ticks |journal=Emerging Infect. Dis. |volume=8 |issue=2 |pages=115–21 |year=2002 |month=February |pmid=11897061 |pmc=2732444 |doi=10.3201/eid0802.010198 |url=http://www.cdc.gov/ncidod/eid/vol8no2/01-0198.htm}}
-*[http://www.cdc.gov/ncidod/eid/vol8no2/01–0198.htm CDC – Vector Interactions and Molecular Adaptations of Lyme Disease and Relapsing Fever Spirochetes Associated with Transmission by Ticks]
 {{DEFAULTSORT:Lyme Disease Microbiology}}