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===Pathogenesis===
===Pathogenesis===
*B. burgdorferi enters bloodstream through saliva during tick bite.<ref name="pmid6859726">{{cite journal| author=Steere AC, Bartenhagen NH, Craft JE, Hutchinson GJ, Newman JH, Rahn DW et al.| title=The early clinical manifestations of Lyme disease. | journal=Ann Intern Med | year= 1983 | volume= 99 | issue= 1 | pages= 76-82 | pmid=6859726 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6859726  }}</ref>
*''[[B. burgdorferi]]'' enters the [[bloodstream]] through [[saliva]] during a tick bite.<ref name="pmid6859726">{{cite journal| author=Steere AC, Bartenhagen NH, Craft JE, Hutchinson GJ, Newman JH, Rahn DW et al.| title=The early clinical manifestations of Lyme disease. | journal=Ann Intern Med | year= 1983 | volume= 99 | issue= 1 | pages= 76-82 | pmid=6859726 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6859726  }}</ref>
*After incubation period (around 3 - 30 days), B. burgdorferi migrates outwards in skin manifesting as erythema chronicum migrans. It is then disseminated to other organs including multiple skin sites manifesting as multiple erythema migrans.<ref name="pmid158674072">{{cite journal|author=Wormser GP, McKenna D, Carlin J, Nadelman RB, Cavaliere LF, Holmgren D et al.|title=Brief communication: hematogenous dissemination in early Lyme disease.|journal=Ann Intern Med|year=2005|volume=142|issue=9|pages=751-5|pmid=15867407|doi=|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15867407}}</ref>
*After the incubation period (around 3-30 days), ''[[B. burgdorferi]]'' migrates outwards in skin, manifesting as erythema chronicum migrans. It is then disseminated to other organs including multiple skin sites manifesting as multiple [[erythema migrans]].<ref name="pmid158674072">{{cite journal|author=Wormser GP, McKenna D, Carlin J, Nadelman RB, Cavaliere LF, Holmgren D et al.|title=Brief communication: hematogenous dissemination in early Lyme disease.|journal=Ann Intern Med|year=2005|volume=142|issue=9|pages=751-5|pmid=15867407|doi=|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15867407}}</ref>
*[[B. burgdorferi]] is very slow growing organism. Its doubling time is 12-24 hours(in contrast [[bacterial]] [[pathogens]] such as [[Streptococcus]] and [[Staphylococcus]], have a doubling time of 20-30 minutes).
*''[[B. burgdorferi]]'' is a very slow growing organism. Its doubling time is 12-24 hours (in contrast with [[bacterial]] [[pathogens]] such as ''[[Streptococcus]]'' and ''[[Staphylococcus]]'', which have a doubling time of 20-30 minutes).
*[[B. burgdorferi]] has an axial filament composed of [[flagella]] that run lengthwise between its [[cell wall]] and [[outer membrane]] like other [[spirochetes]].This structure allows [[B. burgdorferi]] to move efficiently through viscous media(such as [[connective tissue]]) in a corkscrew fashion.
*''[[B. burgdorferi]]'' has an axial filament composed of [[flagella]] that runs lengthwise between its [[cell wall]] and [[outer membrane]] like other [[spirochetes]]. This structure allows ''[[B. burgdorferi]]'' to move efficiently through viscous media (such as [[connective tissue]]) in a corkscrew fashion.
*This helps [[B. burgdorferi]] to [[Disseminated disease|disseminate]] throughout the body in days to weeks after [[infection]].
*This helps ''[[B. burgdorferi]]'' to [[Disseminated disease|disseminate]] throughout the body in the days to weeks after [[infection]].
*[[B. burgdorferi]] penetrates deep into the [[tissue]] where [[immune system]] and [[antibiotics]] are unable to reach.
*''[[B. burgdorferi]]'' penetrates deep into the [[tissue]] where the [[immune system]] and [[antibiotics]] are unable to reach.
*''[[B. burgdorferi]]'' have two [[morphology (biology)|morphological]] forms, i.e. spiral form and [[spheroplast]] form (cysts, granules). The existence of ''[[B. burgdorferi]]'' [[spheroplast]]s, which lacks a [[cell wall]], has been documented in the following models:
*''[[B. burgdorferi]]'' have two [[morphology (biology)|morphological]] forms, a spiral form and a [[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 spiral form requires energy to convert to the altered form i.e. [[spheroplast]] form. This shows that the altered form have a survival function, and it is not merely an end stage [[degeneration]] products.<ref name="Alban" />
* The spiral form requires energy to convert to the [[spheroplast]] form. This shows that the [[spheroplast]] form has a survival function, and it is not merely an end stage [[degeneration]] product.<ref name="Alban" />
* The [[spheroplast]]s are [[virulent]] and [[infectious]] and survives under adverse environmental conditions. Once the conditions are more favourable, they revert back to the spiral form [[in vitro]].<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 [[virulent]] and [[infectious]] and survive under adverse environmental conditions. Once the conditions are more favorable, they revert back to the spiral form [[in vitro]].<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>
* ''[[B. burgdorferi]]'' [[spheroplast]]s plays a key factor in the [[Relapse|relapsing]], persistant nature of [[Lyme disease]] due to:  
* ''[[B. burgdorferi]]'' [[spheroplast]]s plays a key factor in the [[Relapse|relapsing]], persistant nature of [[Lyme disease]] due to:  
**[[Spheroplast]]s have dramatically reduced [[surface area]] for [[immune]] surveillance when compared to spiral form.
**[[Spheroplast]]s have dramatically reduced [[surface area]] for [[immune]] surveillance as compared to spiral form.
**[[Spheroplast]]s express different surface [[proteins]]; As current detects [[antibodies]] to surface [[proteins]] of the spiral form may result in [[seronegative]] disease (i.e. [[Type I and type II errors|false-negative]] [[antibody]] tests).   
**[[Spheroplast]]s express different surface [[proteins]]; as current detects [[antibodies]] to surface [[proteins]] of the spiral form may result in [[seronegative]] disease (i.e. [[Type I and type II errors|false-negative]] [[antibody]] tests).   
**''[[B. burgdorferi]]'' [[spheroplast]]s are generally not susceptible to the [[antibiotics]] traditionally used for [[Lyme disease]]. They have shown sensitivity [[in vitro]] to [[Human parasitic diseases|antiparasitic]] drugs to which the spiral form of ''[[B. burgdorferi]]'' is not sensitive. These drugs includes:
**''[[B. burgdorferi]]'' [[spheroplast]]s are generally not susceptible to the [[antibiotics]] traditionally used for [[Lyme disease]]. They have shown sensitivity [[in vitro]] to [[Human parasitic diseases|antiparasitic]] drugs to which the spiral form of ''[[B. burgdorferi]]'' is not sensitive. These drugs include:
***[[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>

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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 species 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 have two morphological forms, a spiral form and a spheroplast form. Survival strategies of B. burgdorferi include: antigenic variation, physical sequestration, intracellular invasion, and immune system supression.

Pathophysiology

Transmission

Primary Vector

I. scapularis, the primary vector of Lyme disease in Eastern North America - Source: Gross L (2006) A New View on Lyme Disease: Rodents Hold the Key to Annual Risk. PLoS Biol 4(6): e182. https://doi.org/10.1371/journal.pbio.0040182
Relative size of I. scapularis at different life stages - Source: CDC.gov

Other Potential Vectors

Other Modes of Transmission

Reservoir host

  • The primary reservoir host of B. burgdorferi is rodents. These rodents are infested by I. scapularis.
  • The white-footed mouse (Peromyscus leucopus) is the most common rodent infected by B. burgdorferi.[18]
  • Other reservoirs may include voles, chipmunks, squirrels, raccoons, skunks, birds, and reptiles such as lizards.
  • It is predicted that the density of infected nymphal stage of ticks may be lower in areas where predators of primary reservoir hosts, particularly red foxes (Vulpes vulpes), are more active. The reason for this may include:[19]
    • Direct effect: Predation of reservoir hosts.
    • Indirect effect: Decreased movement and increased refuge due to presence of active predator.

Coinfection

  • Ixodes scapularis is also a vector for Anaplasma phagocytophilum (previously referred to as Ehrlichia phagocytophila) and Babesia microti.[20]
  • Anaplasma phagocytophilum causes human granulocytic anaplasmosis (HGA), previously known as human granulocytic ehrlichiosis.
  • Babesia microti causes babesiosis.
  • Sometimes, patients may be coinfected with two or more pathogens.
  • Presence of flu-like symptoms (fever, chills, and headache) in patients of Lyme disease without erythema migrans may indicate concurrent infection with human granulocytic anaplasmosis (HGA) and/or babesiosis.[21]
  • Coinfection should be considered in the case of prolonged flu-like symptoms that fail to respond to Lyme disease treatment.
  • CBC should be considered as initial investigation for patient thought to have coinfection.

Pathogenesis

Mechanisms of persistence

Microscopic pathology

  • Biopsy of erythema migrans shows:
    • Dermal and epidermal involvement in center of lesion
    • Dermal involvement at the periphery

References

  1. ↑ 1.0 1.1 1.2 1.3 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. ↑ 6.0 6.1 Girard YA, Travinsky B, Schotthoefer A, Fedorova N, Eisen RJ, Eisen L, Barbour AG, Lane RS (2009). "Population structure of the lyme borreliosis spirochete Borrelia burgdorferi in the western black-legged tick (Ixodes pacificus) in Northern California". Appl. Environ. Microbiol. 75 (22): 7243–52. doi:10.1128/AEM.01704-09. PMC 2786521. PMID 19783741.
  7. ↑ Sui S, Yang Y, Sun Y, Wang X, Wang G, Shan G, Wang J, Yu J (2017). "On the core bacterial flora of Ixodes persulcatus (Taiga tick)". PLoS ONE. 12 (7): e0180150. doi:10.1371/journal.pone.0180150. PMC 5503197. PMID 28692666.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ Wormser GP, Masters E, Nowakowski J, McKenna D, Holmgren D, Ma K; 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. doi:10.1086/432935. PMID 16142659.
  12. ↑ 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.
  13. ↑ Luger S (1990). "Lyme disease transmitted by a biting fly". N Engl J Med. 322 (24): 1752. PMID 2342543.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ Steere AC (2003-02-01). "Lyme Disease: Questions and Answers" (PDF). Massachusetts General Hospital / Harvard Medical School. Retrieved 2007-03-22.
  17. ↑ 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.
  18. ↑ Anderson JF, Johnson RC, Magnarelli LA, Hyde FW (1986). "Culturing Borrelia burgdorferi from spleen and kidney tissues of wild-caught white-footed mice, Peromyscus leucopus". Zentralbl Bakteriol Mikrobiol Hyg A. 263 (1–2): 34–9. PMID 3577490.
  19. ↑ Hofmeester, Tim R.; Jansen, Patrick A.; Wijnen, Hendrikus J.; Coipan, Elena C.; Fonville, Manoj; Prins, Herbert H. T.; Sprong, Hein; van Wieren, Sipke E. (2017). "Cascading effects of predator activity on tick-borne disease risk". Proceedings of the Royal Society B: Biological Sciences. 284 (1859): 20170453. doi:10.1098/rspb.2017.0453. ISSN 0962-8452.
  20. ↑ Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS; et al. (2006). "The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America". Clin Infect Dis. 43 (9): 1089–134. doi:10.1086/508667. PMID 17029130.
  21. ↑ Krause PJ, McKay K, Thompson CA, Sikand VK, Lentz R, Lepore T; et al. (2002). "Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease". Clin Infect Dis. 34 (9): 1184–91. doi:10.1086/339813. PMID 11941544.
  22. ↑ Steere AC, Bartenhagen NH, Craft JE, Hutchinson GJ, Newman JH, Rahn DW; et al. (1983). "The early clinical manifestations of Lyme disease". Ann Intern Med. 99 (1): 76–82. PMID 6859726.
  23. ↑ Wormser GP, McKenna D, Carlin J, Nadelman RB, Cavaliere LF, Holmgren D; et al. (2005). "Brief communication: hematogenous dissemination in early Lyme disease". Ann Intern Med. 142 (9): 751–5. PMID 15867407.
  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. ↑ 28.0 28.1 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ Murgia R, Cinco M (2004). "Induction of cystic forms by different stress conditions in Borrelia burgdorferi". APMIS. 112 (1): 57–62. PMID 14961976.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ 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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  39. ↑ 39.0 39.1 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.
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