- Lyme disease microbiology
Lyme disease, or borreliosis, is caused by Gram negative spirochetal bacteriafrom the genus" Borrelia", which has at least 37 known species, 12 of which are Lyme related, and an unknown number of genomic strains. "Borrelia" speciesknown 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.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] The strains differ in clinical symptoms and/or presentation as well as geographic distribution.cite book | author = Ryan KJ and Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th ed. | publisher = McGraw Hill | year = 2004 | isbn = 0–8385–8529–9 ]
Except for "Borrelia recurrentis" (which causes louse-borne
relapsing feverand is transmitted by the human body louse), all known species are believed to be transmitted by ticks. [cite book | author = Felsenfeld O |title = "Borrelia": Strains, Vectors, Human and Animal Borreliosis| location = St. Louis | publisher = Warren H. Green, Inc | year = 1971]
pecies and strains
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). 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. There are over 300 species or strains of "Borrelia" worldwide with approximately 100 in the U.S.
* "B. valaisiana" was identified as a genomic species from Strain VS116, and named "B. valaisiana" in 1997. [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=926–932 |year=1997 |pmid=9336888 |doi=] It was later detected by
polymerase chain reaction(PCR) in human cerebral spinal fluid(CSF) in Greece.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] "B. valaisiana" has been isolated throughout Europe, as well east Asia. [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=]
Newly discovered genospecies have also been found to cause disease in humans:
*"B. lusitaniae" 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] in
Europe(especially Portugal), North Africaand Asia.
*"B. bissettii" 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] 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] in the
*"B. spielmanii" 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] 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] in
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 fevergroup 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 Swedenand "I. scapularis" ticks in the U.S.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] 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]
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. 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] "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. 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] There is currently no diagnostic test available for STARI/Masters, and no official treatment protocol, though antibiotics are generally prescribed.
Lyme disease is most endemic in
Northern hemispheretemperate regions. [cite journal | author=Grubhoffer L, Golovchenko M, Vancova M, Zacharovova-Slavickova K, Rudenko N, Oliver JH Jr. | title=Lyme borreliosis: insights into tick-/host-"borrelia" relations | journal=Folia Parasitol (Praha) | year=2005 | month=Nov | volume=52 | issue=4 (Review) | pages=279–294 | pmid=16405291] [cite journal | author=Higgins R | title=Emerging or re-emerging bacterial zoonotic diseases: bartonellosis, leptospirosis, Lyme borreliosis, plague | journal=Rev Sci Tech. | year=2004 | month=Aug | volume=23 | issue=2 | pages=569–581 | pmid=15702720] However, sporadic cases of Lyme disease have been described in other areas of the world.
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 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. [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] 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). [cite web |url=http://www.cdc.gov/ncidod/dvbid/lyme/ld_statistics.htm |title=Lyme Disease Statistics | publisher= Centers for Disease Control and Prevention(CDC) |accessdate=2007-08-23 |date = 2007-04-02]
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] .
"Borrelia burgdorferi" sensu lato infested ticks are being found more frequently in
Japan, as well as in Northwest Chinaand far eastern Russia. [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=Jul | volume=64 | issue=7 | pages=2705–2709] [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=Dec | volume=57 | issue=6 | pages=229–235] "Borrelia" has been isolated in Mongolia as well. [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 Suppl | issue=40 | pages=69–75 | doi=10.1016/j.ijmm.2006.01.031]
South America, tick-borne disease recognition and occurrence is rising. Ticks carrying "Borrelia 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. [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=Apr | volume=40 | issue=4 | pages=443–456] The first reported case of Lyme disease in Brazil was made in 1993 in Sao Paulo. [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] "Borrelia burgdorferi" sensu stricto antigens in patients have been identified in Colombiaand in Bolivia.
Africa, "Borrelia burgdorferi" sensu lato has been identified in Morocco, Algeria, Egyptand Tunisia. [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] [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=Jul | volume=43 | issue=4 | pages=737–742 | doi=10.1603/0022-2585(2006)43 [737:RROLPA] 2.0.CO;2 | doilabel=10.1603/0022-2585(2006)43[737:RROLPA]2.0.CO;2] [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=Aug | volume=30 | number=2 | pages=607–619]
Western Africaand Sub-Saharan Africa, tick-borne relapsing feverhas 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. [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=Sep | volume=60 | issue=3 | pages=155–158] In East Africa two cases of Lyme disease have been reported in Kenya. [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]
Australiathere 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. [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=Feb | volume=21 | issue=1 | pages=109–111 | pmid=2040556 | doi=10.1016/0020-7519(91)90127-S] 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.
The life-cycle of "B. burgdorferi" is complex, requiring
ticks, rodents, and deerat various points. Mice are the primary reservoir for the bacteria; "Ixodes" ticks then transmit the "B. burgdorferi" infectionto 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 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.
The life cycle of the deer tick comprises three growth stages: the
larva, nymphand 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 forms spheroplast-like, straighted non-coiled bacillary forms which are immotile due to flagellin mutations and granular forms coccoid in profile. The model of "Plasmodium" species
Malariawith multiple parasitic profiles demonstrable in various host insects and mammals is a hypothesized model for a similarly complex proposed "Borrelia" spirochete life cycle. [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] [cite web | author= | title=Lymeinfo.net — LDAdverseConditions | url=http://www.lymeinfo.net/medical/LDAdverseConditions.pdf | year=2006|format=PDF]
Whereas "B. burgdorferi" is most associated with
deer tickand the white footed mouse, [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=Oct | volume=108 | issue=4 | pages=322–327 | pmid=727201] "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.
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 contains 910,725 base pairs and 853 genes.cite journal
author=Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, Lathigra R, White O, Ketchum KA, Dodson R, Hickey EK, Gwinn M, Dougherty B, Tomb JF, Fleischmann RD, Richardson D, Peterson J, Kerlavage AR, Quackenbush J, Salzberg S, Hanson M, van Vugt R, Palmer N, Adams MD, Gocayne J, Weidman J, Utterback T, Watthey L, McDonald L, Artiach P, Bowman C, Garland S, Fuji C, Cotton MD, Horst K, Roberts K, Hatch B, Smith HO, and Venter JC | title=Genomic sequence of a Lyme disease spirochaete, "Borrelia burgdorferi" | journal=Nature | volume=190 | issue=6660 | pages=580–586 | year=1997 | url=http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=9403685&dopt=AbstractPlus | accessdate=2007-10-26 | doi=10.1038/37551 | author=Fraser, Claire M. | ] One of the most striking features of "B. burgdorferi" as compared with other
bacteriais its unusual genome, which is far more complex than that of its spirochetal cousin " Treponema pallidum", the agent of syphilis. 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] The genome of "B. burgdorferi" includes a linear chromosomeapproximately one megabasein size, with 21 plasmids(12 linear and 9 circular) – by far the largest number of plasmids found in any known bacterium. 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] Genetic exchange, including plasmid transfers, contributes to the pathogenicityof the organism. 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 U S A | 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] 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.
Chemical analysis of the external membrane of "B. burgdorferi" revealed the presence of 46% proteins, 51% lipids and 3% carbohydrates. [cite journal | url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8348630&query_hl=5&itool=pubmed_docsum | author=Schwarzová K | title=Lyme borreliosis: review of present knowledge | journal=Cesk Epidemiol Mikrobiol Imunol. | year=1993 | month=Jun | volume=42 | issue=2 | pages=87–92]
tructure and growth
"B. burgdorferi" is a highly specialized, motile, two-membrane, flat-waved
spirocheteranging from about 9 to 32 micrometers in length.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=] It is often described as gram-negative, though it stains weakly in the Gram stain. The bacterial membranes in at least the B31, NL303 and N40 strains of "B. burgdorferi" do not contain lipopolysaccharidewhich is extremely atypical for gram-negative bacteria; instead, the membranes contain glycolipids.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] However, the membranes in the B31 strain have been found to contain a lipopolysaccharide-like component.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
accessdate = 2007-10-26|format=PDF] "B. burgdorferi" is a
microaerophilicorganism, requiring little oxygen to survive. Unlike most bacteria, "B. burgdorferi" does not utilize iron, hence avoiding the difficulty of acquiring iron during infection.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=] It lives primarily as an extracellularpathogen, although it can also hide intracellularly (see Mechanisms of persistence section).
Like other spirochetes such as "
T. pallidum" (the agent of syphilis), "B. burgdorferi" has an axial filament composed of flagellawhich run lengthways between its cell wall and outer membrane. This structure allows the spirochete to move efficiently in corkscrew fashion through viscousmedia, 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.
"B. burgdorferi" is very slow growing, with a doubling time of 12–18 hours [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] (in contrast to pathogens such as "
Streptococcus" and " Staphylococcus", which have a doubling time of 20–30 minutes). Since most antibioticskill 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 growth phase, which for "B. burgdorferi" occurs in four-week cycles.Fact|date=April 2007
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
lipoproteinsanchored by N-terminally attached fatty acid molecules to the membrane.cite journal |author=Haake DA |title=Spirochaetal lipoproteins and pathogenesis |journal=Microbiology (Reading, Engl.) |volume=146 (Pt 7) |issue= |pages=1491–1504 |year=2000 |pmid=10878114 |doi=] 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 that they promote the persistence of the spirochete in ticks between blood meals.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=] 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]
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.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=] Virtually all
spirochetesin 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.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] OspB also has an essential role in the adherence of "B. burgdorferi" to the tick gut.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] 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.
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. [cite journal | author=Girschick, J and Singh, SE | title=Molecular survival strategies of the lyme disease spirochete "Borrelia burgdorferi" | month=Sep | year=2004 | journal=The Lancet Infectious Diseases | volume=4 | issue=9 | pages=575–583 | doi=10.1016/S1473-3099(04)01132-6] 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.cite journal | author=Fikrig, E. and Pal, U | title=Adaptation of "Borrelia burgdorferi" in the vector and vertebrate host | journal=Microbes and Infection | volume=5 | issue=7 | month=Jun | year=2003 | pages=659–666 | pmid=12787742 | doi=10.1016/S1286-4579(03)00097-2]
OspE and OspF were initially identified in "B. burgdorferi" strain N40.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=] The "ospE" and "ospF" genes are structurally arranged in tandem as one transcriptional unit under the control of a common promoter. 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.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=] 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.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=] The presence of multiple Erp proteins was proposed to be important in allowing "B. burgdorferi" to evade killing by the alternative complement pathwayof a broad range of potential animal hosts, as individual Erp proteins exhibited different binding patterns to the complement regulator factor Hfrom different animals.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=] However, it was recently demonstrated that the presence of factor His not necessary to enable "B. burgdorferi" to infect mice, suggesting that the Erp proteins have an additional functioncite 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] In 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 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. [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]
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 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.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] 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=355–359 | volume=17 | issue=6 | pmid= 2613324 | doi=10.1007/BF01645543] 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]
Various survival strategies of "B. burgdorferi" have been posited to explain this phenomenon, 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] including the following:
*Physical sequestration of "B. burgdorferi" in sites that are inaccessible to the immune system and antibiotics, such as the
braincite 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=639–649; discussion 673–681 | volume=6 | issue=6 | pmid= 15665404] and central nervous system. New evidence suggests that "B. burgdorferi" may use the host's fibrinolyticsystem to penetrate the blood-brain barrier.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]
"B. burgdorferi" has been shown to invade a variety of cells, including
endothelium,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 | url=http://www.pubmedcentral.gov/picrender.fcgi?artid=257809&blobtype=pdf | format=PDF] fibroblasts,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] lymphocytes,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] macrophages,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] keratinocytes,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] synovium,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] 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] and most recently neuronaland glial cells. 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] By 'hiding' inside these cells, "B. burgdorferi" is able to evade the immune system and is protected to varying degrees against some antibiotics,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] 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] sometimes allowing the infection to persist.
forms, i.e. spheroplasts (cysts, granules).
The existence of "B. burgdorferi" spheroplasts, which lack a
cell wall, has been documented in vitro,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 | year=2000 | pages=119–127 | volume=146 (Pt 1) | pmid= 10658658 | url =http://mic.sgmjournals.org/cgi/content/full/146/1/119] 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=218–226 | volume=24 | issue=3 | pmid= 8811359 | doi=10.1007/BF01781096] 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] 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] in vivo,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] and in an ex vivomodel.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=1747–1754 | volume=191 | issue=10 | pmid= 15838803 | doi=10.1086/429632] The fact that energy is required for the spiral bacterium to convert to the cystic form suggests that these altered forms have a survival function, and are not merely end stage degeneration products. The spheroplasts are indeed virulentand 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.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] 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]
Compared to the spiral form, spheroplasts of "B. burgdorferi" have reduced surface area exposed to immune surveillance. They also express some different surface proteins from spirochetes. "B. burgdorferi" spheroplasts have shown sensitivity in vitro to antiparasitic drugs such as
metronidazole,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] tinidazole,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] and hydroxychloroquinecite 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] to which the spiral form of "B. burgdorferi" is not sensitive.
Antigenic variation and gene expression.
Like the "Borrelia" that cause
relapsing fever, "B. burgdorferi" has the ability to vary its surface proteins in response to immune attack.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=5759–5767 | volume=72 | issue=10 | pmid= 15385475 | url=http://iai.asm.org/cgi/content/full/72/10/5759 | doi=10.1128/IAI.72.10.5759-5767.2004 ] 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. [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=2753–2764 |year=2007 |pmid=17371862 |doi=10.1128/IAI.00037-07]
Complement inhibition, induction of anti-inflammatory
cytokinessuch as IL-10, and the formation of immune complexes have all been documented in "B. burgdorferi" infection. Furthermore, the existence of immune complexes may be involved in seronegativeacute-phase disease (i.e. false-negative antibody tests of bloodand cerebrospinal fluid). One study shows that some acute-phase seronegative Lyme patients have antibodies bound up in these complexes.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]
Advancing immunology research
The role of
T cellsin "Borrelia" was first made in 1984, [cite journal | author=Newman K Jr and Johnson RC | title=T-cell-independent elimination of "Borrelia turicatae" | journal=Infect Immun. | year=1984 month=Sep | volume=45 | issue=3 | pages=572–576] the role of cellular immunity in active Lyme disease was made in 1986, [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] and long term persistence of T cell lymphocyteresponses to "B. burgdorferi" as an "immunological scar syndrome" was hypothesized in 1990. [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] The role Th1and interferon-gamma(IFN-gamma) in "Borrelia" was first described in 1995. [cite journal | 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=Sep | volume=101 | issue=3 | pages=453–460] The cytokinepattern of Lyme disease, and the role of Th1 with down regulation of interleukin-10(IL-10) was first proposed in 1997. [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=Jan | volume=40 | issue=1 | pages=69–79 | doi=10.1002/art.1780400111]
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 immunityand results in Th1 upregulation. These studies have shown a significant decrease in cytokineoutput of (IL-10), an upregulation of Interleukin-6(IL-6) and Interleukin-12(Il-12) and Interferon-gamma(IFN-gamma) and dysregulation in TNF-alphapredominantly.
New research has also found that chronic Lyme patients have higher amounts of "Borrelia"-specific forkhead box P3 (FoxP3) than healthy controls, indicating that
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. [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=Jan | volume=147 | issue=1 | pages=18–27] The signaling pathway P38 mitogen-activated protein kinases(p38 MAP kinase) has also been identified as promoting expression of proinflammatory cytokines from borrelia. [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=Jan | volume=75 | issue=1 | pages=270–277 | date=2006-10-30] [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]
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
autoimmunepattern. [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]
* [http://www.molecularalzheimer.org/Atlasof_borrelia.html Atlas of "Borrelia" (images of spirochetal, spheroplast and granular forms)]
* [http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=138 NCBI Taxonomy Browser – "Borrelia"]
* [http://cmr.tigr.org/tigr-scripts/CMR/GenomePage.cgi?database=gbb "Borrelia burgdorferi" B31 Genome Page]
* [http://cmr.tigr.org/tigr-scripts/CMR/GenomePage.cgi?org=ntbg01 "Borrelia garinii" PBi Genome Page]
* [http://cmr.tigr.org/tigr-scripts/CMR/GenomePage.cgi?org=ntba07 "Borrelia afzelli" PKo Genome Page]
* [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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