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| {{SI}}
| | #REDIRECT[[Borrelia burgdorferi]] |
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| ==Overview==
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| [[Image:Borrelia image.jpg|thumb|left|''Borrelia burgdorferi'' the causative agent of Lyme disease (borreliosis). Magnified 400 times.]]
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| '''[[Lyme disease]]''', or '''borreliosisis''', is caused by [[Gram negative]] [[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.
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| ''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}}</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 ed. | publisher = McGraw Hill | year = 2004 | isbn = 0-8385-8529-9 }}</ref>
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| 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.<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>
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| ==Species and Strains==
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| Until recently it was thought that only three genospecies caused 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). To date the complete [[genome]] of ''B. burgdorferi'' sensu stricto strain B31, B. afzelii strain PKo and B. garinii strain PBi is known. ''B. burgdorferi'' strain B31 was derived by limited dilutional cloning from the original Lyme-disease tick isolate derived by Alan Barbour. There are over 300 species or strains of Borrelia world wide with apx 100 in the U.S. and it is unknown how many cause lyme like sickness, but many of them may.
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| At present, [[diagnostic]] tests are based only on ''B. burgdorferi'' sensu stricto (the only species used in the U.S.), ''B. afzelii'', and ''B. garinii''.
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| ===Emerging Genospecies===
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| * ''B. valaisiana'' was identified as a genomic species from Strain VS116, and named B. valaisiana in 1997.<ref>{{cite journal |author=Wang G, van Dam AP, Le Fleche A, ''et al'' |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=926-32 |year=1997 |pmid=9336888 |doi=}}</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}}</ref> ''B. valaisiana'' has been isolated throughout Europe, as well 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=229-35 |year=2004 |pmid=15623946 |doi=}}</ref>
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| Newly discovered genospecies have also been found to cause disease in humans:
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| *''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 | id=PMID 15004107 | url=http://jcm.asm.org/cgi/reprint/42/3/1316.pdf | format=PDF}}</ref> in Europe (especially Portugal), North Africa and Asia.
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| *''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=3497-504 | volume=36 | issue=12 | id=PMID 9817861 | url=http://jcm.asm.org/cgi/reprint/36/12/3497.pdf | format=PDF}}</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=515-23 | volume=114 | issue=13-14 | id=PMID 12422593}}</ref> in the U.S. and Europe.
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| *''B. 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=873-81 | volume=56 | issue=Pt 4 | id=PMID 16585709}}</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 | id=PMID 16422006 | url=http://www.cdc.gov/ncidod/EID/vol11no11/05-0542.htm}}</ref> in Europe.
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| 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.
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| 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 I. ricinus ticks in Sweden and I. scapularis ticks in the U.S.<!--
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| --><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 | id=PMID 12653133}}</ref><!--
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| --><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 | id=PMID 15498172}}</ref>
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| ===B. lonestari===
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| 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.<!--
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| --><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 | id=PMID 15004069 | url=http://jcm.asm.org/cgi/reprint/42/3/1163.pdf | format=PDF}}</ref><!--
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| --> ''B. lonestari'' is suspected of causing STARI (Southern Tick-Associated Rash Illness), also known as Masters disease in honor of its discoverer Ed Masters. The illness follows a Lone Star tick bite and clinically resembles Lyme disease, but sufferers usually test negative for Lyme.<!--
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| --><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=955-60 | volume=134 | issue=8 | id=PMID 9722725}}</ref>There is currently no diagnostic test available for STARI/Masters, and no official treatment protocol, though antibiotics are generally prescribed.
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| ==Epidemiology==
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| The number of reported cases of the Lyme disease (borreliosis) have been increasing, as are endemic regions in North America. Of cases reported to the United States [[Center for Disease Control]] (CDC), the ratio 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.<ref>{{cite web |url=http://www.cdc.gov/ncidod/dvbid/lyme/ld_UpClimbLymeDis.htm |title=DVBID: Disease Upward Climb - CDC Lyme Disease |accessdate=2007-08-23 |date = 2006-10-02}}</ref> Although Lyme disease has now been reported in 49 of 50 states in the U.S, 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).<ref>{{cite web |url=http://www.cdc.gov/ncidod/dvbid/lyme/ld_statistics.htm |title=Lyme Disease Statistics |accessdate=2007-08-23 |date = 2007-04-02}}</ref>
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| 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 [http://www.eurosurveillance.org/ew/2006/060622.asp Eurosurveillance website].
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| Borrelia burgdoferi sensu lato infested ticks are being found more frequently in Japan, as well as in Northwest China and far eastern Russia.<ref>Li M, Masuzawa T, Takada N, Ishiguro F, Fujita H, Iwaki A, Wang H, Wang J, Kawabata M, Yanagihara Y. "Lyme disease Borrelia species in northeastern China resemble those isolated from far eastern Russia and Japan". Appl Environ Microbiol 1998 Jul;64(7):2705-9</ref><ref>Masuzawa T. "Terrestrial distribution of the Lyme borreliosis agent Borrelia burgdorferi sensu lato in East Asia".Jpn J Infect Dis. 2004 Dec;57(6):229-35</ref> Borrelia has been isolated in Mongolia as well.<ref>Walder G, Lkhamsuren E, Shagdar A, Bataa J, Batmunkh T, Orth D, Heinz FX, Danichova GA, Khasnatinov MA, Wurzner R, Dierich MP."Serological evidence for tick-borne encephalitis, borreliosis, and human granulocytic anaplasmosis in Mongolia."Int J Med Microbiol. 2006 May;296 Suppl 40:69-75.</ref>
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| In South America tick borne disease recognition and occurrence is rising. Ticks carrying Borrelia burgdoferi sensu lato, as well as canine and human tick-borne disease, has been reported widely in Brazil, but the subspecies of borrelia has not yet been defined.<ref>Mantovani E, Costa IP, Gauditano G, Bonoldi VL, Higuchi ML, Yoshinari NH."Description of Lyme disease-like syndrome in Brazil: is it a new tick borne disease or Lyme disease variation?" Braz J Med Biol Res. 2007 Apr;40(4):443-56.</ref> The first reported case of Lyme Disease in Brazil was made in 1993 in Sao Paulo.<ref>Yoshinari NH, Oyafuso LK, Monteiro FG, de Barros PJ, da Cruz FC, Ferreira LG, Bonasser F, Baggio D, Cossermelli W."Lyme disease. Report of a case observed in Brazil" Rev Hosp Clin Fac Med Sao Paulo. 1993 Jul-Aug;48(4):170-4.</ref> Borrelia burgdorferi sensu stricto antigens in patients have been identified in Colombia and in Bolivia.
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| In Northern Africa Borrelia burgdoferi sensu lato has been identified in Morroco, Algeria, Egypt and Tunisia.<ref>Bouattour A, Ghorbel A, Chabchoub A, Postic D. "Lyme borreliosis situation in North Africa" Arch Inst Pasteur Tunis. 2004;81(1-4):13-20</ref><ref>Dsouli N, Younsi-Kabachii H, Postic D, Nouira S, Gern L, Bouattour A. "Reservoir role of lizard Psammodromus algirus in transmission cycle of Borrelia burgdorferi sensu lato (Spirochaetaceae) in Tunisia." J Med Entomol. 2006 Jul;43(4):737-42.</ref><ref>Helmy N. "Seasonal abundance of Ornithodoros (O.) savignyi and prevalence of infection with Borrelia spirochetes in Egypt". J Egypt Soc Parasitol. 2000 Aug;30(2):607-19.</ref>
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| In Western and Sub-Saharan Africa, tick-borne [[relapsing fever]] has been recognized for over a century, 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 that 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>Fivaz BH, Petney TN. "Lyme disease--a new disease in southern Africa?"
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| J S Afr Vet Assoc. 1989 Sep;60(3):155-8.</ref>In East Africa two cases of Lyme disease have been reported in Kenya.<ref>Jowi JO, Gathua SN. Lyme disease: report of two cases. East Afr Med J. 2005 May;82(5):267-9.
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| PMID 16119758</ref>
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| 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.<ref>Piesman J, Stone BF. Vector competence of the Australian paralysis tick, Ixodes holocyclus, for the Lyme disease spirochete Borrelia burgdorferi. Int J Parasitol. 1991 Feb;21(1):109-11.PMID 2040556</ref> Cases of neuroborreliois have been documented in Australia but are often ascribed to travel to other continents. The existence of Lyme disease in Australia is controversial.
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| To date data shows that Northern hemisphere temperate regions are most endemic for Lyme disease.<ref>Grubhoffer L, Golovchenko M, Vancova M, Zacharovova-Slavickova K, Rudenko N, Oliver JH Jr. Lyme borreliosis: insights into tick-/host-borrelia relations. Folia Parasitol (Praha). 2005 Nov;52(4):279-94. Review. PMID 16405291</ref><ref>Higgins R. Emerging or re-emerging bacterial zoonotic diseases: bartonellosis, leptospirosis, Lyme borreliosis, plague. Rev Sci Tech. 2004 Aug;23(2):569-81.PMID 15702720</ref>
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| ==Life cycle==
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| {{see|Tick#Life cycle}}
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| The life-cycle of ''B. burgdorferi'' is complex, requiring ticks, rodents, and deer at various points. Mice are the primary [[Vector (biology)|reservoir]] for the bacteria; [[tick|Ixodes ticks]] then transmit the ''B. burgdorferi'' [[infection]] to deer.
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| 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 come out of 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.
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| The life cycle of the deer tick comprises three growth stages: the larva, nymph and adult.
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| 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 forms [[spheroplast|spheroplast-like]], straighted non-coiled 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.
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| <ref>Macdonald AB. "A life cycle for Borrelia spirochetes?" Med Hypotheses. 2006;67(4):810-8. PMID 16716532</ref>
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| <ref>[http://www.lymeinfo.net/medical/LDAdverseConditions.pdf Lymeinfo.net - LDAdverseConditions]</ref>
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| Whereas B. burgdoferi is most associated with [[deer tick]] and the white footed mouse,<ref>Wallis RC, Brown SE, Kloter KO, Main AJ Jr. Erythema chronicum migrans and lyme arthritis: field study of ticks. Am J Epidemiol. 1978 Oct;108(4):322-7.PMID 727201</ref> B. afzelii is most frequently detected in rodent-feeding vector ticks, 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 pathway of various host species may determine its reservoir host association.
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| ==Genomic characteristics==
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| One of the most striking features of ''B. burgdorferi'' as compared with other [[eubacteria]] is its unusual [[genome]], which is far more complex than that of its spirochetal cousin ''[[Treponema pallidum]]'', the agent of [[syphilis]].<!--
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| --><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 | id=PMID 11254661 | url=http://www.jci.org/cgi/content/full/107/6/651}}</ref>
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| The genome of ''B. burgdorferi'' includes a linear [[chromosome]] approximately one [[megabase]] in size, with 21 [[plasmids]] (12 linear and 9 circular) - by far the largest number of plasmids found in any known bacterium.<!--
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| --><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 | id=PMID 10672174 | url=http://www.blackwell-synergy.com/doi/full/10.1046/j.1365-2958.2000.01698.x}}</ref>
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| Genetic exchange, including plasmid transfers, contributes to the [[pathogenicity]] of the organism.<!--
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| --><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 U S A | year=2004 | pages=14150-5 | volume=101 | issue=39 | id=PMID 15375210 | url=http://www.pnas.org/cgi/reprint/101/39/14150.pdf | format=PDF}}</ref>
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| 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 that the plasmids encode key genes involved in [[virulence]].
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| Chemical analysis of the external membrane of ''B. burgdorferi'' revealed the presence of 46% proteins, 51% lipids and 3% carbohydrates.<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8348630&query_hl=5&itool=pubmed_docsumSchwarzova ]K. "Lyme borreliosis: review of present knowledge"
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| Cesk Epidemiol Mikrobiol Imunol. 1993 Jun;42(2):87-92.</ref>
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| ==Structure and growth==
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| ''B. burgdorferi'' is a highly specialized, motile, two-membrane, spiral-shaped [[spirochete]] ranging from about 9 to 32 [[1 E-6 m|micrometers]] in length. It is often described as [[gram-negative]] and has an outer membrane with [[lipopolysaccharide]] (LPS), though it stains only weakly in the [[Gram stain]]. ''B. burgdorferi'' is a [[microaerophilic]] organism, requiring little oxygen to survive. It lives primarily as an [[extracellular]] pathogen, although it can also hide [[intracellular]]ly (see [[#Mechanisms of persistence|Mechanisms of persistence]] section).
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| Like other spirochetes such as [[T. 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]]. As a result, ''B. burgdorferi'' can disseminate throughout the body within days to weeks of infection, penetrating deeply into tissue where the immune system and antibiotics may not be able to eradicate the infection.
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| ''B. burgdorferi'' is very slow growing, with a doubling time of 12-18 hours<ref>Kelly, R. T. (1984). Genus IV. Borrelia Swellengrebel 1907, 582AL. In Bergey's Manual of Systematic Bacteriology, vol. 1, pp. 57–62. Edited by N. R. Krieg & J. G. Holt. Baltimore: Williams & Wilkins.</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. Antibiotics are most effective during the [[bacterial growth|growth phase]], which for ''B. burgdorferi'' occurs in four-week cycles.
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| ==Outer surface proteins==
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| The outer membrane of Borrelia burgdorferi is composed of various unique outer surface [[lipoproteins|proteins]] (Osp) that have been characterized (OspA through OspF). They are presumed to play a role in virulence.
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| OspA and OspB are by far the most abundant outer surface proteins.
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| 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 evolutionary event. Molecular analysis and sequence comparison of OspA and OspB with other proteins has revealed similarity to the signal [[peptides]] of [[prokaryotic]] [[lipoproteins]].<ref>Bergstrom S. , Bundoc V.G. , Barbour A.G. Molecular analysis of linear plasmid-encoded major surface proteins, OspA and OspB, of the Lyme disease spirochaete Borrelia burgdorferi. Mol. Microbiol. 3 479-486 1989</ref>Virtually all [[spirochetes]] in the midgut of an unfed nymph tick express OspA.
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| OspC is an [[antigen]]-detection of its presence by the host organism and can stimulate an immune response. While each individual bacterial cell contains just one copy of the gene encoding OspC, populations of ''B. burgdorferi'' have shown high levels of variation among individuals in the gene sequence for OspC.<ref>Girschick, J. and Singh, S.E. Molecular survival strategies of the lyme disease spirochete Borrelia burgdorferi. Sep, 2004. The Lancet Infectious Diseases: Volume 4, Issue 9, September 2004, Pages 575-583.</ref> OspC is likely to play a role in transmission from vector to host, since it has been observed that the protein is only expressed in the presence of mammalian blood or tissue.<ref name=Fikrig> Fikrig, E. and Pal, U. Adaptation of Borrelia burgdorferi in the vector and vertebrate host. Microbes and Infection Volume 5, Issue 7, June 2003, Pages 659-666. PMID 12787742</ref>
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| The functions of OspD are unknown.
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| OspE and OspF are structurally arranged in tandem as one transcriptional unit under the control of a common promoter.<ref>Lam TT, Nguyen TP, Montgomery RR, Kantor FS, Fikrig E, Flavell RA. Outer surface proteins E and F of Borrelia burgdorferi, the agent of Lyme disease. Infect Immun. 1994 Jan;62(1):290-8.</ref>
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| In transmission to the mammaliam 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 surface. Simultaneous with the disappearance of OspA, the spirochete population in the midgut begins to express a OspC. Upregulation of OspC begins during the first day of feeding and peaks 48 hours after attachment.<ref>Schwan TG, Piesman J. Temporal changes in outer surface proteins A and C of the Lyme disease-associated spirochete, Borrelia burgdorferi, during the chain of infection in ticks and mice. J Clin Microbiol 2000;38:382-8.</ref>
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| ==Mechanisms of persistence==
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| 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 despite a robust immune response and standard antibiotic treatment, particularly when treatment is delayed and dissemination widespread. Numerous studies have demonstrated 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=347-53 | volume=24 | issue=5 | pmid= 8923044}}</ref><ref name="Preac-Mursic">{{cite journal | author=Preac-Mursic V, Weber K, Pfister HW, ''et al'' | 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}}</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=225-32 | volume=31 | issue=3 | pmid= 10442678}}</ref>
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| Various survival strategies of ''B. burgdorferi'' have been posited to explain this phenomenon,<!--
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| --><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=312-8 | volume=6 | issue=3 | pmid=15065567}}</ref> including the following:
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| *Physical sequestration of ''B. burgdorferi'' in sites that are inaccessible to the immune system and antibiotics, such as the [[brain]]<ref name="Miklossy">{{cite journal | author=Miklossy J, Khalili K, Gern L, ''et al'' | 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=639-49; discussion 673-81 | volume=6 | issue=6 | pmid= 15665404}}</ref> and [[central nervous system]]. New evidence suggests that ''B. 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=1014-22 | volume=73 | issue=2 | pmid= 15664945 | url=http://iai.asm.org/cgi/content/full/73/2/1014}}</ref>
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| *[[Intracellular]] invasion.
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| ''B. burgdorferi'' has been shown to invade a variety of 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=671-8 | volume=59 | issue=2 | pmid= 1987083 | url=http://www.pubmedcentral.gov/picrender.fcgi?artid=257809&blobtype=pdf | format=PDF}}</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=1074-81 | volume=167 | issue=5 | pmid= 8486939}}</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 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=909-15 | 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=Am J Dermatopathol | year=1996 | pages=571-9 | volume=18 | issue=6 | pmid= 8989928}}</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=125-32 | volume=16 | issue=3 | pmid= 8893378}}</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=1025-34 | volume=27 | issue=10 | pmid= 8892586}}</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 | id = PMID 17045505}}</ref> By 'hiding' inside these cells, ''B. burgdorferi'' is able to evade the immune system and is protected to varying degrees against 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=440-4 | volume=166 | issue=2 | pmid= 1634816}}</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=1552-4 | volume=40 | issue=6 | pmid= 8726038 | url=http://aac.asm.org/cgi/reprint/40/6/1552.pdf | format=PDF}}</ref> allowing the infection to persist in a chronic state.
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| *Altered [[morphology (biology)|morphological]] forms, i.e. [[spheroplast]]s (cysts, granules).
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| The existence of ''B. burgdorferi'' spheroplasts, which lack a [[cell wall]], has been documented [[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 | year=2000 | pages=119-27 | volume=146 ( Pt 1) | pmid= 10658658 | url =http://mic.sgmjournals.org/cgi/content/full/146/1/119}}</ref><ref name="Mursic">{{cite journal | author=Mursic VP, Wanner G, Reinhardt S, ''et al'' | title=Formation and cultivation of Borrelia burgdorferi spheroplast-L-form variants | journal=Infection | year=1996 | pages=218-26 | volume=24 | issue=3 | pmid= 8811359}}</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=1127-33 | volume=39 | issue=5 | pmid= 7625800 | url=http://aac.asm.org/cgi/reprint/39/5/1127.pdf | format=PDF}}</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=401-6 | volume=22 | issue=6 | pmid= 7698837}}</ref> [[in vivo]],<ref name="Nanagara" /><ref name="Mursic" /><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=364-7 | volume=26 | issue=6 | pmid= 9861561 | url=http://www.cbc.ca/ideas/features/Aids/phillips.html}}</ref> and in an [[ex vivo]] model.<ref name="Duray">{{cite journal | author=Duray PH, Yin SR, Ito Y, ''et al'' | title=Invasion of human tissue ex vivo by Borrelia burgdorferi | journal=J Infect Dis | year=2005 | pages=1747-54 | volume=191 | issue=10 | pmid= 15838803}}</ref> The fact that energy is required for the spiral bacterium to convert to the cystic form<ref name="Alban" /> suggests that these altered forms have a survival function, and are not merely end stage degeneration products. The spheroplasts are indeed [[virulent]] and [[infectious]], able to survive under adverse environmental conditions, and have been shown to revert back 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=383-8 | volume=109 | issue=5 | pmid= 11478686}}</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}}</ref>
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| A number of other factors make ''B. burgdorferi'' [[spheroplast]]s a key factor in the relapsing, chronic nature of Lyme disease. Compared to the spiral form, spheroplasts have dramatically reduced surface area for immune surveillance. They also express different surface proteins - another reason for [[seronegative]] disease (i.e. [[Type I and type II errors|false-negative]] antibody tests), as current tests only look for antibodies to surface proteins of the ''spiral'' form. In addition, ''B. burgdorferi'' spheroplasts are generally not susceptible to the [[antibiotics]] traditionally used for Lyme disease. They have instead 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=566-76 | volume=107 | issue=6 | pmid= 10379684}}</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=139-42 | volume=7 | issue=2 | pmid= 15248163 | url=http://www.im.microbios.org/26June04/09%20Brorson.pdf | format=PDF}}</ref> and [[hydroxychloroquine]], <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}}</ref> to which the spiral form of ''B. burgdorferi'' is not sensitive.
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| *[[Antigen]]ic variation and [[gene expression]].
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| Like the Borrelia that cause [[relapsing fever]], ''B. burgdorferi'' has the ability to vary its surface proteins in response to [[immune system|immune]] attack.<ref name="Embers" /><ref name="Liang">{{cite journal | author=Liang FT, Yan J, Mbow ML, ''et al'' | title=Borrelia burgdorferi changes its surface antigenic expression in response to host immune responses | journal=Infect Immun | year=2004 | pages=5759-67 | volume=72 | issue=10 | pmid= 15385475 | url=http://iai.asm.org/cgi/content/full/72/10/5759 }}</ref> 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.<ref>{{cite journal |author=Gilmore RD, Howison RR, Schmit VL, ''et al'' |title=Temporal expression analysis of the Borrelia burgdorferi paralogous gene family 54 genes BBA64, BBA65, and BBA66 during persistent infection in mice |journal=Infect. Immun. |volume=75 |issue=6 |pages=2753-64 |year=2007 |pmid=17371862 |doi=10.1128/IAI.00037-07}}</ref>
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| *[[Immune system]] suppression.
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| [[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. burgdorferi'' infection.<ref name="Embers" /> Furthermore, the existence of immune complexes provides another explanation for [[seronegative]] disease (i.e. [[Type I and type II errors|false-negative]] antibody tests of [[blood]] and [[cerebrospinal fluid]]), as studies have shown that substantial numbers of 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=1942-6 | volume=282 | issue=20 | pmid= 10580460}}</ref>
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| ==Advancing Immunology Research==
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| {{See| Lyme Disease#Advancing Immunology Research}}
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| The role of [[T cells]] in borrelia was first made in 1984,<ref>Newman K Jr, Johnson RC."T-cell-independent elimination of Borrelia turicatae".Infect Immun. 1984 Sep;45(3):572-6.</ref> the role of cellular immunity in active Lyme disease was made in 1986,<ref>Dattwyler RJ, Thomas JA, Benach JL, Golightly MG."Cellular immune response in Lyme disease: the response to mitogens, live Borrelia burgdorferi, NK cell function and lymphocyte subsets". Zentralbl Bakteriol Mikrobiol Hyg [A]. 1986 Dec;263(1-2):151-9</ref> and long term persistence of T cell [[lymphocyte]] responses to ''B. burgdorferi'' as an "immunological scar syndrome" was hypothesized in 1990.<ref>Kruger H, Pulz M, Martin R, Sticht-Groh V. "Long-term persistence of specific T- and B-lymphocyte responses to Borrelia burgdorferi following untreated neuroborreliosis".
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| Infection. 1990 Sep-Oct;18(5):263-7.</ref> The role [[Th1]] and [[interferon-gamma]] (INF-gamma) in borrelia was first described in 1995.<ref>Forsberg P, Ernerudh J, Ekerfelt C, Roberg M, Vrethem M, Bergstrom S. "The outer surface proteins of Lyme disease borrelia spirochetes stimulate T cells to secrete interferon-gamma (IFN-gamma): diagnostic and pathogenic implications".
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| Clin Exp Immunol. 1995 Sep;101(3):453-60.</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> Yin Z, Braun J, Neure L, Wu P, Eggens U, Krause A, Kamradt T, Sieper J. "T cell cytokine pattern in the joints of patients with Lyme arthritis and its regulation by cytokines and anticytokines". Arthritis Rheum. 1997 Jan;40(1):69-79.</ref>
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| 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 disregulation in [[TNF-alpha]] predominantly.
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| New research has also found that chronic Lyme patients have higher amounts of Borrelia-specific [[FoxP3|forkhead box P3]] (FoxP3) than healthy controls, indicating that [[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>Jarefors S, Janefjord CK, Forsberg P, Jenmalm MC, Ekerfelt C. "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." Clin Exp Immunol. 2007 Jan;147(1):18-27</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>Olson CM, Hedrick MN, Izadi H, Bates TC, Olivera ER, Anguita J. "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." Infect Immun. 2007 Jan;75(1):270-7. Epub 2006 Oct 30.</ref><ref>Ramesh G, Philipp MT. "Pathogenesis of Lyme neuroborreliosis: mitogen-activated protein kinases Erk1, Erk2, and p38 in the response of astrocytes to Borrelia burgdorferi lipoproteins". Neurosci Lett. 2005 Aug 12-19;384(1-2):112-6</ref>
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| 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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| ==References==
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| {{Reflist|2}}
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| ==External links==
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| *[http://www.molecularalzheimer.org/Atlasof_borrelia.html Atlas of Borrelia (images of spirochetal, spheroplast and granular forms)]
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| *[http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=138 NCBI Taxonomy Browser - Borrelia]
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| *[http://cmr.tigr.org/tigr-scripts/CMR/GenomePage.cgi?database=gbb Borrelia burgdoferi B31 Genome Page]
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| *[http://cmr.tigr.org/tigr-scripts/CMR/GenomePage.cgi?org=ntbg01 Borrelia Garinii PBi Genome Page]
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| *[http://cmr.tigr.org/tigr-scripts/CMR/GenomePage.cgi?org=ntba07 Borrelia Afzelli PKo Gemonme Page]
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| *[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]
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| [[nl:Borrelia burgdorferi]]
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| [[uk:Borrelia burgdorferi]]
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| [[zh:伯氏疏螺旋體]]
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| [[Category:Lyme disease]]
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| [[Category:Spirochaetes]]
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| [[Category:Insect-borne diseases]]
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| [[Category:Zoonoses]]
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| [[Category:Immunology]]
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| [[Category:Infectious disease|Infectious diseases]]
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| [[Category:Microbiology|*]]
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| [[pl:Borrelia burgdorferi]] | |
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