Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Motility and Chemotaxis in the Lyme Spirochete Borrelia burgdorferi: Role in Pathogenesis

라임병 원인 스피로헤타 Borrelia burgdorferi의 운동성과 주화성: 발병기전에서의 역할

  • Yoo, Ah Young (Department of Microbiology, College of Natural Sciences, Pusan National University) ;
  • Kang, Ho Young (Department of Microbiology, College of Natural Sciences, Pusan National University) ;
  • Moon, Ki Hwan (Division of Marine Bioscience, College of Ocean Science and Technology, Korea Maritime and Ocean University)
  • 유아영 (부산대학교 자연과학대학 미생물학과) ;
  • 강호영 (부산대학교 자연과학대학 미생물학과) ;
  • 문기환 (한국해양대학교 해양과학기술대학 해양생명과학부)
  • Received : 2018.05.10
  • Accepted : 2018.05.24
  • Published : 2018.05.30
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Abstract

Motility and chemotaxis are crucial for disease development in many motile pathogens, including spirochetes. In many bacteria, motility is provided by flagella rotation, which is controlled by a chemotaxis-signal-transduction system. Thus, motility and chemotaxis are inextricably linked. Spirochetes are a unique group of bacteria with distinctive flat-wave morphology and corkscrew-like locomotion. This unusual motility pattern is believed to be important for efficient motility within the dense tissues through which these spirochetes preferentially disseminate in a host. Unlike other externally flagellated bacteria-where flagella are in the ambient environment-the flagella of spirochetes are enclosed by the outer membrane and thus are called periplasmic flagella or endoflagella. Although motilityand chemotaxis-associated genes are well studied in some bacteria, the knowledge of how the spirochete achieves complex swimming and the roles of most of the putative spirochetal chemotaxis proteins are still elusive. Recently, cutting-edge imaging methods and unique genetic manipulations in spirochetes have helped to unravel the mystery of motility and chemotaxis in spirochetes. These contemporary advances in understanding the motility and chemotaxis of spirochetes in a host's persistence and disease process are highlighted in this review.

운동성 및 주화성은 스피로헤타를 포함한 많은 병원성 세균의 병원인자로 작용한다. 라임병은 스피로헤타인 Borrelia burgdorferi에 의해 발병하며, 검은다리 참진드기에 물린 상처를 통해 사람에게 전염되는 미국 및 유럽 내에서 가장 유행하는 벡터-매개성 질병이다. Borrelia를 포함한 스피로헤타 균들은 다른 일반적인 편모를 가지는 균들과 달리 주변세포질에 그 편모를 가지며, 운동성이 결여된 돌연변이주의 경우 야생주와 같은 병원성을 가지지 못한다고 알려져 있다. 또한 대장균에 비해 더욱 다양한 종류의 주화성 관련 유전자를 지니고 있어, 편모를 통한 이 균의 운동성이 매우 복잡한 메커니즘을 가질 것으로 예상할 수 있다. 최근 초저온 전자현미경 및 새로운 유전자 조작기술의 발달로 인해 베일에 싸여 있던 스피로헤타의 운동성 및 주화성, 특이한 편모의 구조가 밝혀지고 있다. 본 리뷰 논문에서는 이러한 최첨단 기술의 이용으로 현재까지 밝혀진 Borrelia burgdorferi의 새로운 편모 모터 구조를 소개하고, 균의 병원성과 운동성 및 주화성의 상관관계에 대해 설명하고자 한다.

Keywords

References

  1. Adler, B. and de la Pena Moctezuma, A. 2010. Leptospira and leptospirosis. Vet. Microbiol. 140, 287-296. https://doi.org/10.1016/j.vetmic.2009.03.012
  2. Aldridge, P. and Hughes, K. T. 2002. Regulation of flagellar assembly. Curr. Opin. Microbiol. 5, 160-165. https://doi.org/10.1016/S1369-5274(02)00302-8
  3. Arvikar, S. L. and Steere, A. C. 2015. Diagnosis and treatment of Lyme arthritis. Infect. Dis. Clin. North. Am. 29, 269-280. https://doi.org/10.1016/j.idc.2015.02.004
  4. Bacon, R. M., Kugeler, K. J. and Mead, P. S. Centers for Disease and Prevention (CDC). 2008. Surveillance for Lyme disease--United States, 1992-2006. MMWR. Surveill. Summ. 57, 1-9.
  5. Bakker, R. G., Li, C., Miller, M. R., Cunningham, C. and Charon, N. W. 2007. Identification of specific chemoattractants and genetic complementation of a Borrelia burgdorferi chemotaxis mutant: flow cytometry-based capillary tube chemotaxis assay. Appl. Environ. Microbiol. 73, 1180-1188. https://doi.org/10.1128/AEM.01913-06
  6. Balmelli, T. and Piffaretti, J. C. 1995. Association between different clinical manifestations of Lyme disease and different species of Borrelia burgdorferi sensu lato. Res. Microbiol. 146, 329-340. https://doi.org/10.1016/0923-2508(96)81056-4
  7. Ben-Menachem, G., Kubler-Kielb, J., Coxon, B., Yergey, A. and Schneerson, R. 2003. A newly discovered cholesteryl galactoside from Borrelia burgdorferi. Proc. Natl. Acad. Sci. USA 100, 7913-7918. https://doi.org/10.1073/pnas.1232451100
  8. Bischoff, D. S. and Ordal, G. W. 1992. Bacillus subtilis chemotaxis: a deviation from the Escherichia coli paradigm. Mol. Microbiol. 6, 23-28. https://doi.org/10.1111/j.1365-2958.1992.tb00833.x
  9. Bockenstedt, L. K., Gonzalez, D., Mao, J., Li, M., Belperron, A. A. and Haberman, A. 2014. What ticks do under your skin: two-photon intravital imaging of Ixodes scapularis feeding in the presence of the lyme disease spirochete. Yale. J. Biol. Med. 87, 3-13.
  10. Bockenstedt, L. K. and Wormser, G. P. 2014. Review: unraveling Lyme disease. Arthritis. Rheumatol. 66, 2313-2323. https://doi.org/10.1002/art.38756
  11. Chao, X., Muff, T. J., Park, S. Y., Zhang, S., Pollard, A. M., Ordal, G. W., Bilwes, A. M. and Crane, B. R. 2006. A receptor-modifying deamidase in complex with a signaling phosphatase reveals reciprocal regulation. Cell 124, 561-571. https://doi.org/10.1016/j.cell.2005.11.046
  12. Charon, N. W., Cockburn, A., Li, C., Liu, J., Miller, K. A., Miller, M. R., Motaleb, M. A. and Wolgemuth, C. W. 2012. The unique paradigm of spirochete motility and chemotaxis. Annu. Rev. Microbiol. 66, 349-370. https://doi.org/10.1146/annurev-micro-092611-150145
  13. Charon, N. W. and Goldstein, S. F. 2002. Genetics of motility and chemotaxis of a fascinating group of bacteria: the spirochetes. Annu. Rev. Genet. 36, 47-73. https://doi.org/10.1146/annurev.genet.36.041602.134359
  14. Chen, S., Beeby, M., Murphy, G. E., Leadbetter, J. R., Hendrixson, D. R., Briegel, A., Li, Z., Shi, J., Tocheva, E. I., Muller, A., Dobro, M. J. and Jensen, G. J. 2011. Structural diversity of bacterial flagellar motors. EMBO. J. 30, 2972-2981. https://doi.org/10.1038/emboj.2011.186
  15. Chevance, F. F. and Hughes, K. T. 2008. Coordinating assembly of a bacterial macromolecular machine. Nat. Rev. Microbiol. 6, 455-465. https://doi.org/10.1038/nrmicro1887
  16. Dashper, S. G., Seers, C. A., Tan, K. H. and Reynolds, E. C. 2011. Virulence factors of the oral spirochete Treponema denticola. J. Dent. Res. 90, 691-703. https://doi.org/10.1177/0022034510385242
  17. de Silva, A. M., Telford, S. R. 3rd, Brunet, L. R., Barthold, S. W. and Fikrig, E. 1996. Borrelia burgdorferi OspA is an arthropod-specific transmission-blocking Lyme disease vaccine. J. Exp. Med. 183, 271-275. https://doi.org/10.1084/jem.183.1.271
  18. Dombrowski, C., Kan, W., Motaleb, M. A., Charon, N. W., Goldstein, R. E. and Wolgemuth, C. W. 2009. The elastic basis for the shape of Borrelia burgdorferi. Biophys. J. 96, 4409-4417. https://doi.org/10.1016/j.bpj.2009.02.066
  19. Feng, J., Shi, W., Zhang, S., Sullivan, D., Auwaerter, P. G. and Zhang, Y. 2016. A drug combination screen identifies drugs active against amoxicillin-induced round bodies of in vitro Borrelia burgdorferi persisters from an FDA drug library. Front. Microbiol. 7, 743.
  20. Fraser, C. M., Casjens, S., Huang, W. M., Sutton, G. G., Clayton, R., Lathigra, R., White, O., Ketchum, K. A., Dodson, R., Hickey, E. K., Gwinn, M., Dougherty, B., Tomb, J. F., Fleischmann, R. D., Richardson, D., Peterson, J., Kerlavage, A. R., Quackenbush, J., Salzberg, S., Hanson, M., van Vugt, R., Palmer, N., Adams, M. D., Gocayne, J., Weidman, J., Utterback, T., Watthey, L., McDonald, L., Artiach, P., Bowman, C., Garland, S., Fuji, C., Cotton, M. D., Horst, K., Roberts, K., Hatch, B., Smith, H. O. and Venter, J. C. 1997. Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature 390, 580-586. https://doi.org/10.1038/37551
  21. Garrity, L. F. and Ordal, G. W. 1995. Chemotaxis in Bacillus subtilis: how bacteria monitor environmental signals. Pharmacol. Ther. 68, 87-104. https://doi.org/10.1016/0163-7258(95)00027-5
  22. Ge, Y. and Charon, N. W. 1997. FlaA, a putative flagellar outer sheath protein, is not an immunodominant antigen associated with Lyme disease. Infect. Immun. 65, 2992-2995.
  23. Giacani, L. and Lukehart, S. A. 2014. The endemic treponematoses. Clin. Microbiol. Rev. 27, 89-115. https://doi.org/10.1128/CMR.00070-13
  24. Glekas, G. D., Plutz, M. J., Walukiewicz, H. E., Allen, G. M., Rao, C. V. and Ordal, G. W. 2012. Elucidation of the multiple roles of CheD in Bacillus subtilis chemotaxis. Mol. Microbiol. 86, 743-756. https://doi.org/10.1111/mmi.12015
  25. Goldstein, S. F., Buttle, K. F. and Charon, N. W. 1996. Structural analysis of the Leptospiraceae and Borrelia burgdorferi by high-voltage electron microscopy. J. Bacteriol. 178, 6539-6545. https://doi.org/10.1128/jb.178.22.6539-6545.1996
  26. Goldstein, S. F., Charon, N. W. and Kreiling, J. A. 1994. Borrelia burgdorferi swims with a planar waveform similar to that of eukaryotic flagella. Proc. Natl. Acad. Sci. USA. 91, 3433-3437. https://doi.org/10.1073/pnas.91.8.3433
  27. Guerau-de-Arellano, M. and Huber, B. T. 2002. Development of autoimmunity in Lyme arthritis. Curr. Opin. Rheumatol. 14, 388-393. https://doi.org/10.1097/00002281-200207000-00009
  28. Guyard, C., Raffel, S. J., Schrumpf, M. E., Dahlstrom, E., Sturdevant, D., Ricklefs, S. M., Martens, C., Hayes, S. F., Fischer, E. R., Hansen, B. T., Porcella, S. F. and Schwan, T. G. 2013. Periplasmic flagellar export apparatus protein, FliH, is involved in post-transcriptional regulation of FlaB, motility and virulence of the relapsing fever spirochete Borrelia hermsii. PLoS One 8, e72550. https://doi.org/10.1371/journal.pone.0072550
  29. Haake, D. A. and Levett, P. N. 2015. Leptospirosis in humans. Curr. Top. Microbiol. Immunol. 387, 65-97.
  30. Hazelbauer, G. L. 2012. Bacterial chemotaxis: the early years of molecular studies. Annu. Rev. Microbiol. 66, 285-303. https://doi.org/10.1146/annurev-micro-092611-150120
  31. Herzer, P., Fingerle, V., Pfister, H. W. and Krause, A. 2014. [Lyme borreliosis]. Internist (Berl). 55, 789-802; quiz 803-804. https://doi.org/10.1007/s00108-013-3412-7
  32. Hovind-Hougen, K. 1984. Ultrastructure of spirochetes isolated from Ixodes ricinus and Ixodes dammini. Yale. J. Biol. Med. 57, 543-548.
  33. Karna, S. L., Sanjuan E., Esteve-Gassent, M. D., Miller, C. L., Maruskova, M. and Seshu, J. 2011. CsrA modulates levels of lipoproteins and key regulators of gene expression critical for pathogenic mechanisms of Borrelia burgdorferi. Infect. Immun. 79, 732-744. https://doi.org/10.1128/IAI.00882-10
  34. Ko, A. I., Goarant, C. and Picardeau, M. 2009. Leptospira: the dawn of the molecular genetics era for an emerging zoonotic pathogen. Nat. Rev. Microbiol. 7, 736-747. https://doi.org/10.1038/nrmicro2208
  35. Kristich, C. J. and Ordal, G. W. 2002. Bacillus subtilis CheD is a chemoreceptor modification enzyme required for chemotaxis. J. Biol. Chem. 277, 25356-25362. https://doi.org/10.1074/jbc.M201334200
  36. Kudryashev, M., Cyrklaff, M., Baumeister, W., Simon, M. M., Wallich, R. and Frischknecht, F. 2009. Comparative cryoelectron tomography of pathogenic Lyme disease spirochetes. Mol. Microbiol. 71, 1415-34. https://doi.org/10.1111/j.1365-2958.2009.06613.x
  37. Kuehn, B. M. 2013. CDC estimates 300,000 US cases of Lyme disease annually. JAMA. 310, 1110. https://doi.org/10.1001/jama.2013.278331
  38. Lambert, A., Picardeau, M., Haake, D. A., Sermswan, R. W., Srikram, A., Adler, B. and Murray, G. A. 2012. FlaA proteins in Leptospira interrogans are essential for motility and virulence but are not required for formation of the flagellum sheath. Infect. Immun. 80, 2019-2025. https://doi.org/10.1128/IAI.00131-12
  39. Li, C., Bakker, R. G., Motaleb, M. A., Sartakova, M. L., Cabello, F. C. and Charon, N. W. 2002. Asymmetrical flagellar rotation in Borrelia burgdorferi nonchemotactic mutants. Proc. Natl. Acad. Sci. USA. 99, 6169-6174. https://doi.org/10.1073/pnas.092010499
  40. Liao, S., Sun, A., Ojcius, D. M., Wu, S., Zhao, J. and Yan, J. 2009. Inactivation of the fliY gene encoding a flagellar motor switch protein attenuates mobility and virulence of Leptospira interrogans strain Lai. BMC. Microbiol. 9, 253. https://doi.org/10.1186/1471-2180-9-253
  41. Lin, T., Gao L., Zhang, C., Odeh, E., Jacobs, M. B., Coutte, L., Chaconas, G., Philipp, M. T. and Norris, S. J. 2012. Analysis of an ordered, comprehensive STM mutant library in infectious Borrelia burgdorferi: insights into the genes required for mouse infectivity. PLoS One 7, e47532. https://doi.org/10.1371/journal.pone.0047532
  42. Liu, J., Lin, T., Botkin, D. J., McCrum, E., Winkler, H. and Norris, S. J. 2009. Intact flagellar motor of Borrelia burgdorferi revealed by cryo-electron tomography: evidence for stator ring curvature and rotor/C-ring assembly flexion. J. Bacteriol. 191, 5026-5036. https://doi.org/10.1128/JB.00340-09
  43. Lux, R., Miller, J. N., Park, N. H. and Shi, W. 2001. Motility and chemotaxis in tissue penetration of oral epithelial cell layers by Treponema denticola. Infect. Immun. 69, 6276-6283. https://doi.org/10.1128/IAI.69.10.6276-6283.2001
  44. Moon, K. H., Hobbs, G. and Motaleb, M. A. 2016. Borrelia burgdorferi CheD Promotes Various Functions in Chemotaxis and the Pathogenic Life Cycle of the Spirochete. Infect. Immun. 84, 1743-1752. https://doi.org/10.1128/IAI.01347-15
  45. Moon, K. H., Zhao, X., Manne, A., Wang, J., Yu, Z., Liu, J. and Motaleb, M. A. 2016. Spirochetes flagellar collar protein FlbB has astounding effects in orientation of periplasmic flagella, bacterial shape, motility, and assembly of motors in Borrelia burgdorferi. Mol. Microbiol. 102, 336-348. https://doi.org/10.1111/mmi.13463
  46. Motaleb, M. A., Corum, L., Bono, J. L., Elias, A. F., Rosa, P., Samuels, D. S. and Charon, N. W. 2000. Borrelia burgdorferi periplasmic flagella have both skeletal and motility functions. Proc. Natl. Acad. Sci. USA. 97, 10899-10904. https://doi.org/10.1073/pnas.200221797
  47. Motaleb, M. A., Liu, J. and Wooten, R. M. 2015. Spirochetal motility and chemotaxis in the natural enzootic cycle and development of Lyme disease. Curr. Opin. Microbiol. 28, 106-113. https://doi.org/10.1016/j.mib.2015.09.006
  48. Motaleb, M. A., Miller, M. R., Li, C., Bakker, R. G., Goldstein, S. F., Silversmith, R. E., Bourret, R. B. and Charon, N. W. 2005. CheX is a phosphorylated CheY phosphatase essential for Borrelia burgdorferi chemotaxis. J. Bacteriol. 187, 7963-7969. https://doi.org/10.1128/JB.187.23.7963-7969.2005
  49. Motaleb, M. A., Miller, M. R., Li, C. and Charon, N. W. 2007. Phosphorylation assays of chemotaxis two-component system proteins in Borrelia burgdorferi. Methods. Enzymol. 422, 438-447.
  50. Motaleb, M. A., Pitzer, J. E., Sultan, S. Z. and Liu, J. 2011. A novel gene inactivation system reveals altered periplasmic flagellar orientation in a Borrelia burgdorferi fliL mutant. J. Bacteriol. 193, 3324-3331. https://doi.org/10.1128/JB.00202-11
  51. Motaleb, M. A., Sal, M. S. and Charon, N. W. 2004. The decrease in FlaA observed in a flaB mutant of Borrelia burgdorferi occurs posttranscriptionally. J. Bacteriol. 186, 3703-3711. https://doi.org/10.1128/JB.186.12.3703-3711.2004
  52. Motaleb, M. A., Sultan, S. Z., Miller, M. R., Li, C. and Charon, N. W. 2011. CheY3 of Borrelia burgdorferi is the key response regulator essential for chemotaxis and forms a long-lived phosphorylated intermediate. J. Bacteriol. 193, 3332-3341. https://doi.org/10.1128/JB.00362-11
  53. Muff, T. J. and Ordal, G. W. 2007. The CheC phosphatase regulates chemotactic adaptation through CheD. J. Biol. Chem. 282, 34120-34128. https://doi.org/10.1074/jbc.M706432200
  54. Murray, T. S. and Shapiro, E. D. 2010. Lyme disease. Clin. Lab. Med. 30, 311-328. https://doi.org/10.1016/j.cll.2010.01.003
  55. Novak, E. A., Sekar, P., Xu, H., Moon, K. H., Manne, A., Wooten, R. M. and Motaleb, M. A. 2016. The Borrelia burgdorferi CheY3 response regulator is essential for chemotaxis and completion of its natural infection cycle. Cell. Microbiol. 18, 1782-1799. https://doi.org/10.1111/cmi.12617
  56. Novak, E. A., Sultan, S. Z. and Motaleb, M. A. 2014. The cyclic-di-GMP signaling pathway in the Lyme disease spirochete, Borrelia burgdorferi. Front. Cell. Infect. Microbiol. 4, 56.
  57. Ohnishi, J., Piesman, J. and de Silva, A. M. 2001. Antigenic and genetic heterogeneity of Borrelia burgdorferi populations transmitted by ticks. Proc. Natl. Acad. Sci. USA. 98, 670-675. https://doi.org/10.1073/pnas.98.2.670
  58. Pal, U., Li, X., Wang, T., Montgomery, R. R., Ramamoorthi, N., Desilva, A. M., Bao, F., Yang, X., Pypaert, M., Pradhan, D., Kantor, F. S., Telford, S., Anderson, J. F. and Fikrig, E. 2004. TROSPA, an Ixodes scapularis receptor for Borrelia burgdorferi. Cell 119, 457-468. https://doi.org/10.1016/j.cell.2004.10.027
  59. Park, S. Y., Lowder, B., Bilwes, A. M., Blair, D. F. and Crane, B. R. 2006. Structure of FliM provides insight into assembly of the switch complex in the bacterial flagella motor. Proc. Natl. Acad. Sci. USA. 103, 11886-11891. https://doi.org/10.1073/pnas.0602811103
  60. Pitzer, J. E., Sultan, S. Z., Hayakawa, Y., Hobbs, G., Miller, M. R. and Motaleb, M. A. 2011. Analysis of the Borrelia burgdorferi cyclic-di-GMP-binding protein PlzA reveals a role in motility and virulence. Infect. Immun. 79, 1815-1825. https://doi.org/10.1128/IAI.00075-11
  61. Porter, S. L., Wadhams, G. H. and Armitage, J. P. 2011. Signal processing in complex chemotaxis pathways. Nat. Rev. Microbiol. 9, 153-165. https://doi.org/10.1038/nrmicro2505
  62. Radolf, J. D., Caimano, M. J., Stevenson, B. and Hu, L. T. 2012. Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes. Nat. Rev. Microbiol. 10, 87-99. https://doi.org/10.1038/nrmicro2714
  63. Rollend, L., Fish, D. and Childs, J. E. 2013. Transovarial transmission of Borrelia spirochetes by Ixodes scapularis: a summary of the literature and recent observations. Ticks. Tick. Borne. Dis. 4, 46-51. https://doi.org/10.1016/j.ttbdis.2012.06.008
  64. Rosa, P. A., Tilly, K. and Stewart, P. E. 2005. The burgeoning molecular genetics of the Lyme disease spirochaete. Nat. Rev. Microbiol. 3, 129-143. https://doi.org/10.1038/nrmicro1086
  65. Rosey, E. L., Kennedy, M. J. and Yancey, R. J. Jr. 1996. Dual flaA1 flaB1 mutant of Serpulina hyodysenteriae expressing periplasmic flagella is severely attenuated in a murine model of swine dysentery. Infect. Immun. 64, 4154-4162.
  66. Sal, M. S., Li, C., Motalab, M. A., Shibata, S., Aizawa, S. and Charon, N. W. 2008. Borrelia burgdorferi uniquely regulates its motility genes and has an intricate flagellar hook-basal body structure. J. Bacteriol. 190, 1912-1921. https://doi.org/10.1128/JB.01421-07
  67. Sanchez, J. L. 2015. Clinical manifestations and treatment of lyme disease. Clin. Lab. Med. 35, 765-778. https://doi.org/10.1016/j.cll.2015.08.004
  68. Sanjuan, E., Esteve-Gassent, M. D., Maruskova, M. and Seshu, J. 2009. Overexpression of CsrA (BB0184) alters the morphology and antigen profiles of Borrelia burgdorferi. Infect. Immun. 77, 5149-5162. https://doi.org/10.1128/IAI.00673-09
  69. Sapi, E., Kaur, N., Anyanwu, S., Luecke, D. F., Datar, A., Patel, S., Rossi, M. and Stricker, R. B. 2011. Evaluation of in-vitro antibiotic susceptibility of different morphological forms of Borrelia burgdorferi. Infect. Drug. Resist. 4, 97-113.
  70. Sarkar, M. K., Paul, K. and Blair, D. 2010. Chemotaxis signaling protein CheY binds to the rotor protein FliN to control the direction of flagellar rotation in Escherichia coli. Proc. Natl. Acad. Sci. USA. 107, 9370-9375. https://doi.org/10.1073/pnas.1000935107
  71. Schwan, T. G. and Piesman, J. 2000. Temporal changes in outer surface proteins A and C of the lyme disease-associated spirochete, Borrelia burgdorferi, during the chain of infection in ticks and mice. J. Clin. Microbiol. 38, 382-388.
  72. Shih, C. M., Chao, L. L. and Yu, C. P. 2002. Chemotactic migration of the Lyme disease spirochete (Borrelia burgdorferi) to salivary gland extracts of vector ticks. Am. J. Trop. Med. Hyg. 66, 616-621. https://doi.org/10.4269/ajtmh.2002.66.616
  73. Smith, R. P., Schoen, R. T., Rahn, D. W., Sikand, V. K., Nowakowski, J., Parenti, D. L., Holman, M. S., Persing, D. H. and Steere, A. C. 2002. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann. Intern. Med. 136, 421-428. https://doi.org/10.7326/0003-4819-136-6-200203190-00005
  74. Sourjik, V. and Wingreen, N. S. 2012. Responding to chemical gradients: bacterial chemotaxis. Curr. Opin. Cell. Biol. 24, 262-268. https://doi.org/10.1016/j.ceb.2011.11.008
  75. Steere, A. C., Duray, P. H. and Butcher, E. C. 1988. Spirochetal antigens and lymphoid cell surface markers in Lyme synovitis. Comparison with rheumatoid synovium and tonsillar lymphoid tissue. Arthritis. Rheum. 31, 487-495. https://doi.org/10.1002/art.1780310405
  76. Steere, A. C., Gross, D., Meyer, A. L. and Huber, B. T. 2001. Autoimmune mechanisms in antibiotic treatment-resistant lyme arthritis. J. Autoimmun. 16, 263-268. https://doi.org/10.1006/jaut.2000.0495
  77. Sultan, S. Z., Manne, A., Stewart, P. E., Bestor, A., Rosa, P. A., Charon. N. W. and Motaleb, M. A. 2013. Motility is crucial for the infectious life cycle of Borrelia burgdorferi. Infect. Immun. 81, 2012-2021. https://doi.org/10.1128/IAI.01228-12
  78. Sultan, S. Z., Pitzer, J. E., Boquoi, T., Hobbs, G., Miller, M. R. and Motaleb, M. A. 2011. Analysis of the HD-GYP domain cyclic dimeric GMP phosphodiesterase reveals a role in motility and the enzootic life cycle of Borrelia burgdorferi. Infect. Immun. 79, 3273-3283. https://doi.org/10.1128/IAI.05153-11
  79. Sultan, S. Z., Pitzer, J. E., Miller, M. R. and Motaleb, M. A. 2010. Analysis of a Borrelia burgdorferi phosphodiesterase demonstrates a role for cyclic-di-guanosine monophosphate in motility and virulence. Mol. Microbiol. 77, 128-142. https://doi.org/10.1111/j.1365-2958.2010.07191.x
  80. Sultan, S. Z., Sekar, P., Zhao, X., Manne, A., Liu, J., Wooten, R. M. and Motaleb, M. A. 2015. Motor rotation is essential for the formation of the periplasmic flagellar ribbon, cellular morphology, and Borrelia burgdorferi persistence within Ixodes scapularis tick and murine hosts. Infect. Immun. 83, 1765-1777. https://doi.org/10.1128/IAI.03097-14
  81. Sze, C. W. and Li, C. 2011. Inactivation of bb0184, which encodes carbon storage regulator A, represses the infectivity of Borrelia burgdorferi. Infect. Immun. 79, 1270-1279. https://doi.org/10.1128/IAI.00871-10
  82. Sze, C. W., Morado, D. R., Liu, J., Charon, N. W., Xu, H. and Li, C. 2011. Carbon storage regulator A (CsrA(Bb)) is a repressor of Borrelia burgdorferi flagellin protein FlaB. Mol. Microbiol. 82, 851-864. https://doi.org/10.1111/j.1365-2958.2011.07853.x
  83. Sze, C. W., Zhang, K., Kariu, T., Pal, U. and Li, C. 2012. Borrelia burgdorferi needs chemotaxis to establish infection in mammals and to accomplish its enzootic cycle. Infect. Immun. 80, 2485-2492. https://doi.org/10.1128/IAI.00145-12
  84. van Dam, A. P., Kuiper, H., Vos, K., Widjojokusumo, A., de Jongh, B. M., Spanjaard, L., Ramselaar, A. C., Kramer, M. D. and Dankert, J. 1993. Different genospecies of Borrelia burgdorferi are associated with distinct clinical manifestations of Lyme borreliosis. Clin. Infect. Dis. 17, 708-717. https://doi.org/10.1093/clinids/17.4.708
  85. van Leeuwenhoek, A. 1684. An abstract of a letter from Mr. Anthony Leevvenhoeck at Delft, dated Sep. 17. 1683. Containing some microscopical observations, about animals in the scurf of the teeth, the substance call'd worms in the nose, the cuticula consisting of scales. Philos. Trans. 14, 568-574. https://doi.org/10.1098/rstl.1684.0030
  86. Xu, H., Raddi, G., Liu, J., Charon, N. W. and Li, C. 2011. Chemoreceptors and flagellar motors are subterminally located in close proximity at the two cell poles in spirochetes. J. Bacteriol. 193, 2652-2656. https://doi.org/10.1128/JB.01530-10
  87. Xu, H., Sultan, S., Yerke, A., Moon, K. H., Wooten, R. M. and Motaleb, M. A. 2017. Borrelia burgdorferi CheY2 is dispensable for chemotaxis or motility but crucial for the infectious life cycle of the spirochete. Infect. Immun. 85, e00264-16.
  88. Xue, F., Yan, J. and Picardeau, M. 2009. Evolution and pathogenesis of Leptospira spp.: lessons learned from the genomes. Microbes Infect. 11, 328-333. https://doi.org/10.1016/j.micinf.2008.12.007
  89. Zhang, K., Liu, J., Tu, Y., Xu, H., Charon, N. W. and Li, C. 2012. Two CheW coupling proteins are essential in a chemosensory pathway of Borrelia burgdorferi. Mol. Microbiol. 85, 782-794. https://doi.org/10.1111/j.1365-2958.2012.08139.x
  90. Zhao, X., Norris, S. J. and Liu, J. 2014. Molecular architecture of the bacterial flagellar motor in cells. Biochemistry 53, 4323-4333. https://doi.org/10.1021/bi500059y
  91. Zhao, X., Zhang, K., Boquoi, T., Hu, B., Motaleb, M. A., Miller, K. A., James, M. E., Charon, N. W., Manson, M. D., Norris, S. J., Li, C. and Liu, J. 2013. Cryoelectron tomog raphy reveals the sequential assembly of bacterial flagella in Borrelia burgdorferi. Proc. Natl. Acad. Sci. USA. 110, 14390-14395. https://doi.org/10.1073/pnas.1308306110