Lyme disease pathophysiology: Difference between revisions

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*Hard-bodied [[tick]]s of the [[genus]] ''[[Ixodes]]'' are the primary [[vector (biology)|vectors]] of [[Lyme disease]].
*Hard-bodied [[tick]]s of the [[genus]] ''[[Ixodes]]'' are the primary [[vector (biology)|vectors]] of [[Lyme disease]].
*Majority of [[Ixodes]]-[[Vector|vectored]] human disease are caused by ''[[I. scapularis]]'', ''I. pacificus'', ''[[I. ricinus]]'', and ''I. persulcatus''. So, they are also known as 'bridge' [[vectors]].<ref name="pmid21890064">{{cite journal| author=Rudenko N, Golovchenko M, Grubhoffer L, Oliver JH| title=Updates on Borrelia burgdorferi sensu lato complex with respect to public health. | journal=Ticks Tick Borne Dis | year= 2011 | volume= 2 | issue= 3 | pages= 123-8 | pmid=21890064 | doi=10.1016/j.ttbdis.2011.04.002 | pmc=3167092 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21890064  }} </ref>
*Majority of [[Ixodes]]-[[Vector|vectored]] human disease are caused by ''[[I. scapularis]]'', ''I. pacificus'', ''[[I. ricinus]]'', and ''I. persulcatus''. So, they are also known as 'bridge' [[vectors]].<ref name="pmid21890064">{{cite journal| author=Rudenko N, Golovchenko M, Grubhoffer L, Oliver JH| title=Updates on Borrelia burgdorferi sensu lato complex with respect to public health. | journal=Ticks Tick Borne Dis | year= 2011 | volume= 2 | issue= 3 | pages= 123-8 | pmid=21890064 | doi=10.1016/j.ttbdis.2011.04.002 | pmc=3167092 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21890064  }} </ref>
*Adult ticks are more infected then nymph stage by pathogens infectious to humans.<ref name="SchwartzFish1997">{{cite journal|last1=Schwartz|first1=Ira|last2=Fish|first2=Durland|last3=Daniels|first3=Thomas J.|title=Prevalence of the Rickettsial Agent of Human Granulocytic Ehrlichiosis in Ticks from a Hyperendemic Focus of Lyme Disease|journal=New England Journal of Medicine|volume=337|issue=1|year=1997|pages=49–50|issn=0028-4793|doi=10.1056/NEJM199707033370111}}</ref> But the majority of infections are caused by ticks in the nymph stage during late spring and summer.<ref name="pmid10206627">{{cite journal| author=Falco RC, McKenna DF, Daniels TJ, Nadelman RB, Nowakowski J, Fish D et al.| title=Temporal relation between Ixodes scapularis abundance and risk for Lyme disease associated with erythema migrans. | journal=Am J Epidemiol | year= 1999 | volume= 149 | issue= 8 | pages= 771-6 | pmid=10206627 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10206627  }} </ref>
*[[Prevalence]] of [[infection]] in adult [[ticks]] are more then nymph stage by [[pathogens]] [[infectious]] to humans.<ref name="SchwartzFish1997">{{cite journal|last1=Schwartz|first1=Ira|last2=Fish|first2=Durland|last3=Daniels|first3=Thomas J.|title=Prevalence of the Rickettsial Agent of Human Granulocytic Ehrlichiosis in Ticks from a Hyperendemic Focus of Lyme Disease|journal=New England Journal of Medicine|volume=337|issue=1|year=1997|pages=49–50|issn=0028-4793|doi=10.1056/NEJM199707033370111}}</ref> But the majority of [[infections]] are caused by [[ticks]] in the nymph stage during late spring and summer.<ref name="pmid10206627">{{cite journal| author=Falco RC, McKenna DF, Daniels TJ, Nadelman RB, Nowakowski J, Fish D et al.| title=Temporal relation between Ixodes scapularis abundance and risk for Lyme disease associated with erythema migrans. | journal=Am J Epidemiol | year= 1999 | volume= 149 | issue= 8 | pages= 771-6 | pmid=10206627 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10206627  }} </ref>
*In most cases, the tick must be attached for 36 to 48 hours or more before the spirochetes can be transmitted.<ref name="pmid2010643">{{cite journal| author=Piesman J, Maupin GO, Campos EG, Happ CM| title=Duration of adult female Ixodes dammini attachment and transmission of Borrelia burgdorferi, with description of a needle aspiration isolation method. | journal=J Infect Dis | year= 1991 | volume= 163 | issue= 4 | pages= 895-7 | pmid=2010643 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2010643  }} </ref>. It takes atleast 36 hours for spirohetes to multiply and migrate to salivary glands from mid gut.<ref name="pmid11209063">{{cite journal| author=Ohnishi J, Piesman J, de Silva AM| title=Antigenic and genetic heterogeneity of Borrelia burgdorferi populations transmitted by ticks. | journal=Proc Natl Acad Sci U S A | year= 2001 | volume= 98 | issue= 2 | pages= 670-5 | pmid=11209063 | doi=10.1073/pnas.98.2.670 | pmc=14646 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11209063  }} </ref>
*In most cases, the [[tick]] must be attached for 36 to 48 hours or more before the [[spirochetes]] can be [[Transmission|transmitted]].<ref name="pmid2010643">{{cite journal| author=Piesman J, Maupin GO, Campos EG, Happ CM| title=Duration of adult female Ixodes dammini attachment and transmission of Borrelia burgdorferi, with description of a needle aspiration isolation method. | journal=J Infect Dis | year= 1991 | volume= 163 | issue= 4 | pages= 895-7 | pmid=2010643 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2010643  }} </ref>. It takes atleast 36 hours for [[spirohetes]] to multiply and migrate to [[salivary glands]] from [[midgut]].<ref name="pmid11209063">{{cite journal| author=Ohnishi J, Piesman J, de Silva AM| title=Antigenic and genetic heterogeneity of Borrelia burgdorferi populations transmitted by ticks. | journal=Proc Natl Acad Sci U S A | year= 2001 | volume= 98 | issue= 2 | pages= 670-5 | pmid=11209063 | doi=10.1073/pnas.98.2.670 | pmc=14646 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11209063  }} </ref>
*In Europe and Pacific region of North America, the commonly known sheep tick, castor bean tick, or European castor bean tick (''[[Ixodes ricinus]]'') is the transmitter.<ref name="pmid21890064">{{cite journal| author=Rudenko N, Golovchenko M, Grubhoffer L, Oliver JH| title=Updates on Borrelia burgdorferi sensu lato complex with respect to public health. | journal=Ticks Tick Borne Dis | year= 2011 | volume= 2 | issue= 3 | pages= 123-8 | pmid=21890064 | doi=10.1016/j.ttbdis.2011.04.002 | pmc=3167092 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21890064  }} </ref>
*In Europe and Pacific region of North America, the commonly known [[Ixodes ricinus|sheep tick]], [[Ixodes ricinus|castor bean tick]], or [[Ixodes ricinus|European castor bean tick]] (''[[Ixodes ricinus]]'') is the transmitter.<ref name="pmid21890064">{{cite journal| author=Rudenko N, Golovchenko M, Grubhoffer L, Oliver JH| title=Updates on Borrelia burgdorferi sensu lato complex with respect to public health. | journal=Ticks Tick Borne Dis | year= 2011 | volume= 2 | issue= 3 | pages= 123-8 | pmid=21890064 | doi=10.1016/j.ttbdis.2011.04.002 | pmc=3167092 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21890064  }} </ref>
*In North America, the black-legged tick or deer tick (''Ixodes scapularis'') has been identified as the key to the disease's spread on the east coast.  
*In North America, [[Ixodes scapularis|the black-legged tick]] or [[Ixodes scapularis|deer tick]] (''[[Ixodes scapularis]]'') has been identified as the key to the disease's spread on the east coast.  
*About 20% of individuals infected with Lyme disease by the deer tick are aware of having had any tick bite, making early detection difficult in the absence of a rash.<ref name="Wormser">{{cite journal | author=Wormser G, Masters E, Nowakowski J, ''et al'' | title=Prospective clinical evaluation of patients from missouri and New York with erythema migrans-like skin lesions. | journal=Clin Infect Dis | volume=41 | issue=7 | pages=958-65 | year=2005 | pmid= 16142659}}</ref>
*Only 20% of individuals [[Infection|infected]] with [[Lyme disease]] by the [[Ixodes scapularis|deer tick]] are aware of having had any [[tick]] bite, making early detection difficult in the absence of a [[rash]].<ref name="Wormser">{{cite journal | author=Wormser G, Masters E, Nowakowski J, ''et al'' | title=Prospective clinical evaluation of patients from missouri and New York with erythema migrans-like skin lesions. | journal=Clin Infect Dis | volume=41 | issue=7 | pages=958-65 | year=2005 | pmid= 16142659}}</ref>


====Other Potential Vectors====
====Other Potential Vectors====
*The lone star tick (''Amblyomma americanum''), which is found throughout the southeastern U.S. as far west as Texas, and increasingly in northeastern states as well.<ref name="Clark">{{cite journal | author=Clark K | title=''Borrelia'' species in host-seeking ticks and small mammals in northern Florida. | journal=J Clin Microbiol | volume=42 | issue=11 | pages=5076-86 | year=2004 | pmid= 15528699 | url=http://jcm.asm.org/cgi/reprint/42/11/5076.pdf | format=PDF}}</ref>
*The [[Amblyomma americanum|lone star tick]] (''[[Amblyomma americanum]]''), which is found throughout the southeastern U.S. as far west as Texas, and increasingly in northeastern states as well.<ref name="Clark">{{cite journal | author=Clark K | title=''Borrelia'' species in host-seeking ticks and small mammals in northern Florida. | journal=J Clin Microbiol | volume=42 | issue=11 | pages=5076-86 | year=2004 | pmid= 15528699 | url=http://jcm.asm.org/cgi/reprint/42/11/5076.pdf | format=PDF}}</ref>
*These tick bites usually go unnoticed due to the small size of the tick in its nymphal stage, as well as tick secretions that prevent the host from feeling any itch or pain from the bite.
*These [[tick]] bites usually go unnoticed due to the small size of the [[tick]] in its nymphal stage, as well as [[tick]] [[secretions]] that prevent the host from feeling any [[itch]] or [[pain]] from the bite.
*It was once thought to be a vector, although recent studies demonstrate that this tick species is not a competent vector of ''Borrelia burgdorferi'' sensu lato.<ref name="Ledin-k">{{cite journal | author = Ledin K, Zeidner N, Ribeiro J, "et al" | title = Borreliacidal activity of saliva of the tick Amblyomma americanum. | journal = Med Vet Entomol | volume = 19 | issue = 1 | pages = 90-95 | year = 2005 | pmid = 15752182}}</ref>  
*It was once thought to be a [[vector,]] although recent studies demonstrate that this [[tick]] species is not a competent [[vector]] of ''[[Borrelia burgdorferi]]'' sensu lato.<ref name="Ledin-k">{{cite journal | author = Ledin K, Zeidner N, Ribeiro J, "et al" | title = Borreliacidal activity of saliva of the tick Amblyomma americanum. | journal = Med Vet Entomol | volume = 19 | issue = 1 | pages = 90-95 | year = 2005 | pmid = 15752182}}</ref>  


====Other Modes of Transmission====
====Other Modes of Transmission====
*While Lyme spirochetes have been found in insects other than ticks, reports of actual infectious transmission appear to be rare.<ref name="Magnarelli">{{cite journal | author=Magnarelli L, Anderson J | title=Ticks and biting insects infected with the etiologic agent of Lyme disease, ''Borrelia burgdorferi''. | journal=J Clin Microbiol | volume=26 | issue=8 | pages=1482-6 | year=1988 | pmid= 3170711 | url=http://www.pubmedcentral.gov/picrender.fcgi?artid=266646&blobtype=pdf | format=PDF}}</ref><ref name="Luger">{{cite journal | author=Luger S | title=Lyme disease transmitted by a biting fly. | journal=N Engl J Med | volume=322 | issue=24 | pages=1752 | year=1990 | pmid = 2342543 | url=http://cassia.org/library/N_Engl_J_Med_1990_Jun_14,322(24),1752.htm}}</ref>  
*While [[Lyme]] [[spirochetes]] have been found in insects other than [[ticks]], reports of actual [[infectious]] [[transmission]] appear to be rare.<ref name="Magnarelli">{{cite journal | author=Magnarelli L, Anderson J | title=Ticks and biting insects infected with the etiologic agent of Lyme disease, ''Borrelia burgdorferi''. | journal=J Clin Microbiol | volume=26 | issue=8 | pages=1482-6 | year=1988 | pmid= 3170711 | url=http://www.pubmedcentral.gov/picrender.fcgi?artid=266646&blobtype=pdf | format=PDF}}</ref><ref name="Luger">{{cite journal | author=Luger S | title=Lyme disease transmitted by a biting fly. | journal=N Engl J Med | volume=322 | issue=24 | pages=1752 | year=1990 | pmid = 2342543 | url=http://cassia.org/library/N_Engl_J_Med_1990_Jun_14,322(24),1752.htm}}</ref>  
*[[Sexually transmitted infection|Sexual transmission]] have been reported; Lyme spirochetes have been found in semen and breast milk, however transmission of the spirochete by these routes is not known to occur.<ref name="Bach">{{cite conference | author=Bach G | title=Recovery of Lyme spirochetes by PCR in semen samples of previously diagnosed Lyme disease patients. | booktitle=14th International Scientific Conference on Lyme Disease | year=2001 | url=http://www.anapsid.org/lyme/bach.html}}</ref><ref name="Schmidt">{{cite journal | author=Schmidt B, Aberer E, Stockenhuber C, ''et al'' | title=Detection of ''Borrelia burgdorferi'' DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis. | journal=Diagn Microbiol Infect Dis | volume=21 | issue=3 | pages=121-8 | year=1995 | pmid = 7648832}}</ref><ref name="Steere_2003">{{cite web | author = Steere AC | title = Lyme Disease: Questions and Answers |publisher = Massachusetts General Hospital / Harvard Medical School | url = http://www.mgh.harvard.edu/medicine/rheu/Q&ALYME.pdf | format = PDF | date = 2003-02-01 | accessdate = 2007-03-22}}</ref>
*[[Sexually transmitted infection|Sexual transmission]] have been reported; [[Lyme]] [[spirochetes]] have been found in [[semen]] and [[breast milk]], however [[transmission]] of the [[spirochete]]e by these routes is not known to occur.<ref name="Bach">{{cite conference | author=Bach G | title=Recovery of Lyme spirochetes by PCR in semen samples of previously diagnosed Lyme disease patients. | booktitle=14th International Scientific Conference on Lyme Disease | year=2001 | url=http://www.anapsid.org/lyme/bach.html}}</ref><ref name="Schmidt">{{cite journal | author=Schmidt B, Aberer E, Stockenhuber C, ''et al'' | title=Detection of ''Borrelia burgdorferi'' DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis. | journal=Diagn Microbiol Infect Dis | volume=21 | issue=3 | pages=121-8 | year=1995 | pmid = 7648832}}</ref><ref name="Steere_2003">{{cite web | author = Steere AC | title = Lyme Disease: Questions and Answers |publisher = Massachusetts General Hospital / Harvard Medical School | url = http://www.mgh.harvard.edu/medicine/rheu/Q&ALYME.pdf | format = PDF | date = 2003-02-01 | accessdate = 2007-03-22}}</ref>
*Congenital transmission of Lyme disease can occur from an infected mother to [[fetus]] through the [[placenta]] during pregnancy. However, prompt antibiotic treatment appears to prevent fetal harm.<ref>{{cite journal |author=Walsh CA, Mayer EW, Baxi LV |title=Lyme disease in pregnancy: case report and review of the literature |journal=Obstetrical & gynecological survey |volume=62 |issue=1 |pages=41-50 |year=2007 |pmid=17176487 |doi=10.1097/01.ogx.0000251024.43400.9a}}</ref>
*[[Congenital]] [[transmission]] of [[Lyme disease]] can occur from an [[infection|infected]] mother to [[fetus]] through the [[placenta]] during [[pregnancy]]. However, prompt [[antibiotic]] treatment appears to prevent [[fetal]] harm.<ref>{{cite journal |author=Walsh CA, Mayer EW, Baxi LV |title=Lyme disease in pregnancy: case report and review of the literature |journal=Obstetrical & gynecological survey |volume=62 |issue=1 |pages=41-50 |year=2007 |pmid=17176487 |doi=10.1097/01.ogx.0000251024.43400.9a}}</ref>


===Pathogenesis===
===Pathogenesis===
* ''B. burgdorferi'' has been shown to invade a variety of cells, including:
* ''[[B. burgdorferi]]'' has been shown to [[Invasion|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
**[[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
<nowiki>[[Fibroblasts]]</nowiki><nowiki><ref name="Klempner-b"></nowiki>{{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>
<nowiki>[[Fibroblasts]]</nowiki><nowiki><ref name="Klempner-b"></nowiki>{{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>
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**[[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>
**[[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>
**[[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>  
**[[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, allowing the infection to persist.<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>  
* By 'hiding' inside these [[cells]], ''[[B. burgdorferi]]'' is able to evade the [[immune system ]] and is protected to varying degrees against [[antibiotics]], allowing the [[infection]] to persist.<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>  
*''B. burgdorferi'' altered [[morphology (biology)|morphological]] forms, i.e. [[spheroplast]]s (cysts, granules). The existence of ''B. burgdorferi'' spheroplasts, which lack a [[cell wall]], has been documented in the following models:
*''[[B. burgdorferi]]'' alteres [[morphology (biology)|morphological]] forms, i.e. spiral form and [[spheroplast]] form (cysts, granules). The existence of ''[[B. burgdorferi]]'' [[spheroplast]]s, which lack a [[cell wall]], has been documented in the following models:
**[[In vitro]] model<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 vitro]] model<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]] model<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>
**[[In vivo]] model<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>
**[[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>  
**[[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 suggests that these altered forms have a survival function, and are not merely end stage degeneration products.<ref name="Alban" />
* The fact that energy is required for the spiral form to convert to the cystic form suggests that these altered form have a survival function, and are not merely end stage [[degeneration]] products.<ref name="Alban" />
* 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>
* The [[spheroplast]]s 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>
 
* A number of other factors make ''[[B. burgdorferi]]'' [[spheroplast]]s a key factor in the [[Relapse|relapsing]], persistant nature of [[Lyme disease]].   
* A number of other factors make ''B. burgdorferi'' [[spheroplast]]s a key factor in the relapsing, persistant nature of Lyme disease.   
* Compared to the spiral form, [[spheroplast]]s have dramatically reduced [[surface area]] for [[immune]] surveillance.   
* 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.   
* 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]]'' [[spheroplast]]s 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  to which the spiral form of ''[[B. burgdorferi]]'' is not sensitive. Drugs such as:
* 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  to which the spiral form of ''B. burgdorferi'' is not sensitive. 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>
**[[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>
**[[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>
**[[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>  
**[[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>  


====Mechanisms of persistence====
====Mechanisms of persistence====
*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="pmid15065567">{{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 | volume= 6 | issue= 3 | pages= 312-8 | pmid=15065567 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15065567  }} </ref><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>  
*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="pmid15065567">{{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 | volume= 6 | issue= 3 | pages= 312-8 | pmid=15065567 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15065567  }} </ref><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 presistant 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>
* This ability is related to the [[genomic]] complexity of ''[[B. burgdorferi]]'', and is another way ''[[B. burgdorferi]]'' evades the [[immune system]] to establish a presistant [[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>
*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>
*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 [[Disseminated disease|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>
*Various survival strategies of ''B. burgdorferi'' have been posted to explain this phenomenon, including the following:<ref name="pmid15065567" />
*Various survival strategies of ''[[B. burgdorferi]]'' have been posted to explain this phenomenon, including the following:<ref name="pmid15065567" />
**Physical Sequestration
**Physical Sequestration
***Physical sequestration of ''B. burgdorferi'' in sites that are inaccessible to the immune system and antibiotics, such as the [[brain]] and [[central nervous system]].<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>
***Physical sequestration of ''[[B. burgdorferi]]'' in sites that are inaccessible to the [[immune system]] and [[antibiotics]], such as the [[brain]] and [[central nervous system]].<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>
***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>
***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>
**[[Immune system]] suppression
**[[Immune system]] suppression
***[[Complement system|Complement]] inhibition, induction of anti-inflammatory [[cytokines]] such as [[Interleukin 10|IL-10]], and the formation of [[immune complex]]es have all been documented in ''B. burgdorferi'' infection.<ref name="pmid15065567" />
***[[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="pmid15065567" />
***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>
***Furthermore, the existence of [[Immune complex|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 [[Immune complex|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>


==References==
==References==

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Overview

Lyme disease is caused by Borrelia burgdorferi and is transmitted primarily by tick named Ixodes scapularis. Ticks can attach to any part of the human body but are often found in hard-to-see areas such as the groin, armpits, and scalp. In most cases, the tick must be attached for 36 to 48 hours or more before the spirochetes can be transmitted. Very few people affected with Lyme disease recall a tick bite. B. burgdorferi is known to invade a variety of cells in humans. By 'hiding' inside these cells, B. burgdorferi is able to evade the immune system and is protected to varying degrees against antibiotics. B. burgdorferi altered morphological forms, i.e. spheroplasts (cysts, granules). B. burgdorferi has the ability to vary its surface proteins in response to immune attack. Various survival strategies of B. burgdorferi includes physical sequestration in tissues and immune system suppression.

Pathophysiology

Transmission

Ixodes scapularis, the primary vector of Lyme disease in eastern North America.
Ixodes scapularis, the primary vector of Lyme disease in eastern North America.


Primary Vector

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Other Modes of Transmission

Pathogenesis

Mechanisms of persistence

References

  1. ↑ 1.0 1.1 Rudenko N, Golovchenko M, Grubhoffer L, Oliver JH (2011). "Updates on Borrelia burgdorferi sensu lato complex with respect to public health". Ticks Tick Borne Dis. 2 (3): 123–8. doi:10.1016/j.ttbdis.2011.04.002. PMC 3167092. PMID 21890064.
  2. ↑ Schwartz, Ira; Fish, Durland; Daniels, Thomas J. (1997). "Prevalence of the Rickettsial Agent of Human Granulocytic Ehrlichiosis in Ticks from a Hyperendemic Focus of Lyme Disease". New England Journal of Medicine. 337 (1): 49–50. doi:10.1056/NEJM199707033370111. ISSN 0028-4793.
  3. ↑ Falco RC, McKenna DF, Daniels TJ, Nadelman RB, Nowakowski J, Fish D; et al. (1999). "Temporal relation between Ixodes scapularis abundance and risk for Lyme disease associated with erythema migrans". Am J Epidemiol. 149 (8): 771–6. PMID 10206627.
  4. ↑ Piesman J, Maupin GO, Campos EG, Happ CM (1991). "Duration of adult female Ixodes dammini attachment and transmission of Borrelia burgdorferi, with description of a needle aspiration isolation method". J Infect Dis. 163 (4): 895–7. PMID 2010643.
  5. ↑ Ohnishi J, Piesman J, de Silva AM (2001). "Antigenic and genetic heterogeneity of Borrelia burgdorferi populations transmitted by ticks". Proc Natl Acad Sci U S A. 98 (2): 670–5. doi:10.1073/pnas.98.2.670. PMC 14646. PMID 11209063.
  6. ↑ Wormser G, Masters E, Nowakowski J; et al. (2005). "Prospective clinical evaluation of patients from missouri and New York with erythema migrans-like skin lesions". Clin Infect Dis. 41 (7): 958–65. PMID 16142659.
  7. ↑ Clark K (2004). "Borrelia species in host-seeking ticks and small mammals in northern Florida" (PDF). J Clin Microbiol. 42 (11): 5076–86. PMID 15528699.
  8. ↑ Ledin K, Zeidner N, Ribeiro J; et al. (2005). "Borreliacidal activity of saliva of the tick Amblyomma americanum". Med Vet Entomol. 19 (1): 90–95. PMID 15752182.
  9. ↑ Magnarelli L, Anderson J (1988). "Ticks and biting insects infected with the etiologic agent of Lyme disease, Borrelia burgdorferi" (PDF). J Clin Microbiol. 26 (8): 1482–6. PMID 3170711.
  10. ↑ Luger S (1990). "Lyme disease transmitted by a biting fly". N Engl J Med. 322 (24): 1752. PMID 2342543.
  11. ↑ Bach G (2001). "Recovery of Lyme spirochetes by PCR in semen samples of previously diagnosed Lyme disease patients.". 14th International Scientific Conference on Lyme Disease.
  12. ↑ Schmidt B, Aberer E, Stockenhuber C; et al. (1995). "Detection of Borrelia burgdorferi DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis". Diagn Microbiol Infect Dis. 21 (3): 121–8. PMID 7648832.
  13. ↑ Steere AC (2003-02-01). "Lyme Disease: Questions and Answers" (PDF). Massachusetts General Hospital / Harvard Medical School. Retrieved 2007-03-22.
  14. ↑ Walsh CA, Mayer EW, Baxi LV (2007). "Lyme disease in pregnancy: case report and review of the literature". Obstetrical & gynecological survey. 62 (1): 41–50. doi:10.1097/01.ogx.0000251024.43400.9a. PMID 17176487.
  15. ↑ Ma Y, Sturrock A, Weis JJ (1991). "Intracellular localization of Borrelia burgdorferi within human endothelial cells" (PDF). Infect Immun. 59 (2): 671–8. PMID 1987083.</ref [[Fibroblasts]]<ref name="Klempner-b">Klempner MS, Noring R, Rogers RA (1993). "Invasion of human skin fibroblasts by the Lyme disease spirochete, Borrelia burgdorferi". J Infect Dis. 167 (5): 1074–81. PMID 8486939.
  16. ↑ Dorward DW, Fischer ER, Brooks DM (1997). "Invasion and cytopathic killing of human lymphocytes by spirochetes causing Lyme disease". Clin Infect Dis. 25 Suppl 1: S2–8. PMID 9233657.
  17. ↑ Montgomery RR, Nathanson MH, Malawista SE (1993). "The fate of Borrelia burgdorferi, the agent for Lyme disease, in mouse macrophages. Destruction, survival, recovery". J Immunol. 150 (3): 909–15. PMID 8423346.
  18. ↑ Aberer E, Kersten A, Klade H, Poitschek C, Jurecka W (1996). "Heterogeneity of Borrelia burgdorferi in the skin". Am J Dermatopathol. 18 (6): 571–9. PMID 8989928.
  19. ↑ Girschick HJ, Huppertz HI, Russmann H, Krenn V, Karch H (1996). "Intracellular persistence of Borrelia burgdorferi in human synovial cells". Rheumatol Int. 16 (3): 125–32. PMID 8893378.
  20. ↑ 20.0 20.1 Nanagara R, Duray PH, Schumacher HR Jr (1996). "Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic Lyme disease: possible factors contributing to persistence of organisms". Hum Pathol. 27 (10): 1025–34. PMID 8892586.
  21. ↑ Livengood JA, Gilmore RD (2006). "Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi". Microbes Infect. [Epub ahead of print]. PMID 17045505.
  22. ↑ Georgilis K, Peacocke M, Klempner MS (1992). "Fibroblasts protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro". J Infect Dis. 166 (2): 440–4. PMID 1634816.
  23. ↑ Brouqui P, Badiaga S, Raoult D (1996). "Eucaryotic cells protect Borrelia burgdorferi from the action of penicillin and ceftriaxone but not from the action of doxycycline and erythromycin" (PDF). Antimicrob Agents Chemother. 40 (6): 1552–4. PMID 8726038.
  24. ↑ 24.0 24.1 Alban PS, Johnson PW, Nelson DR (2000). "Serum-starvation-induced changes in protein synthesis and morphology of Borrelia burgdorferi". Microbiology. 146 ( Pt 1): 119–27. PMID 10658658.
  25. ↑ 25.0 25.1 Mursic VP, Wanner G, Reinhardt S; et al. (1996). "Formation and cultivation of Borrelia burgdorferi spheroplast-L-form variants". Infection. 24 (3): 218–26. PMID 8811359.
  26. ↑ Kersten A, Poitschek C, Rauch S, Aberer E (1995). "Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi" (PDF). Antimicrob Agents Chemother. 39 (5): 1127–33. PMID 7625800.
  27. ↑ Schaller M, Neubert U (1994). "Ultrastructure of Borrelia burgdorferi after exposure to benzylpenicillin". Infection. 22 (6): 401–6. PMID 7698837.
  28. ↑ Phillips SE, Mattman LH, Hulinska D, Moayad H (1998). "A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated". Infection. 26 (6): 364–7. PMID 9861561.
  29. ↑ Duray PH, Yin SR, Ito Y; et al. (2005). "Invasion of human tissue ex vivo by Borrelia burgdorferi". J Infect Dis. 191 (10): 1747–54. PMID 15838803.
  30. ↑ Gruntar I, Malovrh T, Murgia R, Cinco M (2001). "Conversion of Borrelia garinii cystic forms to motile spirochetes in vivo". APMIS. 109 (5): 383–8. PMID 11478686.
  31. ↑ Murgia R, Cinco M (2004). "Induction of cystic forms by different stress conditions in Borrelia burgdorferi". APMIS. 112 (1): 57–62. PMID 14961976.
  32. ↑ Brorson O, Brorson SH (1999). "An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to metronidazole". APMIS. 107 (6): 566–76. PMID 10379684.
  33. ↑ Brorson O, Brorson SH (2004). "An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to tinidazole" (PDF). Int Microbiol. 7 (2): 139–42. PMID 15248163.
  34. ↑ Brorson O, Brorson SH (2002). "An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to hydroxychloroquine". Int Microbiol. 5 (1): 25–31. PMID 12102233.
  35. ↑ 35.0 35.1 35.2 Embers ME, Ramamoorthy R, Philipp MT (2004). "Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease". Microbes Infect. 6 (3): 312–8. PMID 15065567.
  36. ↑ Liang FT, Yan J, Mbow ML; et al. (2004). "Borrelia burgdorferi changes its surface antigenic expression in response to host immune responses". Infect Immun. 72 (10): 5759–67. PMID 15385475.
  37. ↑ Gilmore RD, Howison RR, Schmit VL; et al. (2007). "Temporal expression analysis of the Borrelia burgdorferi paralogous gene family 54 genes BBA64, BBA65, and BBA66 during persistent infection in mice". Infect. Immun. 75 (6): 2753–64. doi:10.1128/IAI.00037-07. PMID 17371862.
  38. ↑ Bayer ME, Zhang L, Bayer MH (1996). "Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms. A PCR study of 97 cases". Infection. 24 (5): 347–53. PMID 8923044.
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  40. ↑ Oksi J, Marjamaki M, Nikoskelainen J, Viljanen MK (1999). "Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis". Ann Med. 31 (3): 225–32. PMID 10442678.
  41. ↑ Miklossy J, Khalili K, Gern L; et al. (2004). "Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease". J Alzheimers Dis. 6 (6): 639–49, discussion 673-81. PMID 15665404.
  42. ↑ Grab DJ, Perides G, Dumler JS, Kim KJ, Park J, Kim YV, Nikolskaia O, Choi KS, Stins MF, Kim KS (2005). "Borrelia burgdorferi, host-derived proteases, and the blood-brain barrier". Infect Immun. 73 (2): 1014–22. PMID 15664945.
  43. ↑ Schutzer SE, Coyle PK, Reid P, Holland B (1999). "Borrelia burgdorferi-specific immune complexes in acute Lyme disease". JAMA. 282 (20): 1942–6. PMID 10580460.


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