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Genetic Manipulation of Borrelia Spp.

  • Dan Drecktrah
  • D. Scott Samuels
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 415)

Abstract

The spirochetes Borrelia (Borreliella) burgdorferi and Borrelia hermsii, the etiologic agents of Lyme disease and relapsing fever, respectively, cycle in nature between an arthropod vector and a vertebrate host. They have extraordinarily unusual genomes that are highly segmented and predominantly linear. The genetic analyses of Lyme disease spirochetes have become increasingly more sophisticated, while the age of genetic investigation in the relapsing fever spirochetes is just dawning. Molecular tools available for B. burgdorferi and related species range from simple selectable markers and gene reporters to state-of-the-art inducible gene expression systems that function in the animal model and high-throughput mutagenesis methodologies, despite nearly overwhelming experimental obstacles. This armamentarium has empowered borreliologists to build a formidable genetic understanding of the cellular physiology of the spirochete and the molecular pathogenesis of Lyme disease.

Notes

Acknowledgements

We thank Ben Adler for thoughtful reading of the manuscript and Darrin Akins, Jim Battisti, Melissa Caimano, Sherwood Casjens, George Chaconas, Christian Eggers, Frank Gherardini, Mike Gilbert, Laura Hall, Chris Li, Meghan Lybecker, Rich Marconi, Motaleb, Steve Norris, Justin Radolf, Sandy Raffel, Patti Rosa, Tom Schwan, Jon Skare, Phil Stewart, Kit Tilly, and Frank Yang for useful discussions about the genetic manipulation of Borrelia. Our laboratory is supported by National Institutes of Health grant AI051486 (to D.S.S.).

References

  1. Adams PP, Flores Avile C, Jewett MW (2017a) A dual luciferase reporter system for B. burgdorferi measures transcriptional activity during tick-pathogen interactions. Front Cell Infect Microbiol 7:225Google Scholar
  2. Adams PP, Flores Avile C, Popitsch N, Bilusic I, Schroeder R, Lybecker M, Jewett MW (2017b) In vivo expression technology and 5′ end mapping of the Borrelia burgdorferi transcriptome identify novel RNAs expressed during mammalian infection. Nucleic Acids Res 45:775–792CrossRefPubMedGoogle Scholar
  3. Alverson J, Samuels DS (2002) groEL expression in gyrB mutants of Borrelia burgdorferi. J Bacteriol 184:6069–6072PubMedCentralPubMedCrossRefGoogle Scholar
  4. Alverson J, Bundle SF, Sohaskey CD, Lybecker MC, Samuels DS (2003) Transcriptional regulation of the ospAB and ospC promoters from Borrelia burgdorferi. Mol Microbiol 48:1665–1677CrossRefPubMedGoogle Scholar
  5. Arnold WK, Savage CR, Brissette CA, Seshu J, Livny J, Stevenson B (2016) RNA-seq of Borrelia burgdorferi in multiple phases of growth reveals insights into the dynamics of gene expression, transcriptome architecture, and noncoding RNAs. PLoS ONE 11:e0164165PubMedCentralPubMedCrossRefGoogle Scholar
  6. Babb K, McAlister JD, Miller JC, Stevenson B (2004) Molecular characterization of Borrelia burgdorferi erp promoter/operator elements. J Bacteriol 186:2745–2756PubMedCentralPubMedCrossRefGoogle Scholar
  7. Bandy NJ, Salman-Dilgimen A, Chaconas G (2014) Construction and characterization of a Borrelia burgdorferi strain with conditional expression of the essential telomere resolvase, ResT. J Bacteriol 196:2396–2404PubMedCentralPubMedCrossRefGoogle Scholar
  8. Barbour AG, Guo BP (2010) Pathogenesis of relapsing fever. In Samuels DS, Radolf JD (eds) Borrelia: Molecular biology, host interaction and pathogenesis. Norfolk, UK Caister Academic Press, pp 333–357Google Scholar
  9. Barthold SW, Cadavid D, Philipp MT (2010) Animal models of borreliosis. In Samuels DS, Radolf JD (eds) Borrelia: Molecular biology, host interaction and pathogenesis. Norfolk, UK Caister Academic Press, pp 359–411Google Scholar
  10. Battisti JM, Raffel SJ, Schwan TG (2008). A system for site-specific genetic manipulation of the relapsing fever spirochete Borrelia hermsii. In DeLeo FR, Otto M (eds) Bacterial pathogenesis: Methods and protocols. Totowa, New Jersey Humana Press, pp 69–84Google Scholar
  11. Beaurepaire C, Chaconas G (2005) Mapping of essential replication functions of the linear plasmid lp17 of B. burgdorferi by targeted deletion walking. Mol Microbiol 57:132–142CrossRefPubMedGoogle Scholar
  12. Bestor A, Stewart PE, Jewett MW, Sarkar A, Tilly K, Rosa PA (2010) Use of the Cre-lox recombination system to investigate the lp54 gene requirement in the infectious cycle of Borrelia burgdorferi. Infect Immun 78:2397–2407PubMedCentralPubMedCrossRefGoogle Scholar
  13. Blevins JS, Revel AT, Smith AH, Bachlani GN, Norgard MV (2007) Adaptation of a luciferase gene reporter and lac expression system to Borrelia burgdorferi. Appl Environ Microbiol 73:1501–1513PubMedCentralPubMedCrossRefGoogle Scholar
  14. Bono JL, Elias AF, Kupko JJ III, Stevenson B, Tilly K, Rosa P (2000) Efficient targeted mutagenesis in Borrelia burgdorferi. J Bacteriol 182:2445–2452PubMedCentralPubMedCrossRefGoogle Scholar
  15. Botkin DJ, Abbott AN, Stewart PE, Rosa PA, Kawabata H, Watanabe H, Norris SJ (2006) Identification of potential virulence determinants by Himar1 transposition of infectious Borrelia burgdorferi B31. Infect Immun 74:6690–6699PubMedCentralPubMedCrossRefGoogle Scholar
  16. Boylan JA, Posey JE, Gherardini FC (2003) Borrelia oxidative stress response regulator, BosR: a distinctive Zn-dependent transcriptional activator. Proc Natl Acad Sci USA 100:11684–11689CrossRefPubMedGoogle Scholar
  17. Brisson D, Drecktrah D, Eggers CH, Samuels DS (2012) Genetics of Borrelia burgdorferi. Annu Rev Genet 46:515–536CrossRefPubMedGoogle Scholar
  18. Bugrysheva JV, Bryksin AV, Godfrey HP, Cabello FC (2005) Borrelia burgdorferi rel is responsible for generation of guanosine-3′-diphosphate-5′-triphosphate and growth control. Infect Immun 73:4972–4981PubMedCentralPubMedCrossRefGoogle Scholar
  19. Burtnick MN, Downey JS, Brett PJ, Boylan JA, Frye JG, Hoover TR, Gherardini FC (2007) Insights into the complex regulation of rpoS in Borrelia burgdorferi. Mol Microbiol 65:277–293PubMedCentralPubMedCrossRefGoogle Scholar
  20. Byram R, Stewart PE, Rosa P (2004) The essential nature of the ubiquitous 26-kilobase circular replicon of Borrelia burgdorferi. J Bacteriol 186:3561–3569PubMedCentralPubMedCrossRefGoogle Scholar
  21. Cabello FC, Dubytska L, Bryksin AV, Bugrysheva JV, Godfrey HP (2006). Genetic studies of the Borrelia burgdorferi bmp gene family. In Cabello FC, Hulinska D, Godfrey HP (eds) Molecular Biology of Spirochetes. Amsterdam, Netherlands IOS Press, pp 235–249Google Scholar
  22. Caimano MJ, Eggers CH, Hazlett KRO, Radolf JD (2004) RpoS is not central to the general stress response in Borrelia burgdorferi but does control expression of one or more essential virulence determinants. Infect Immun 72:6433–6445PubMedCentralPubMedCrossRefGoogle Scholar
  23. Caimano MJ, Iyer R, Eggers CH, Gonzalez C, Morton EA, Gilbert MA, Schwartz I, Radolf JD (2007) Analysis of the RpoS regulon in Borrelia burgdorferi in response to mammalian host signals provides insight into RpoS function during the enzootic cycle. Mol Microbiol 65:1193–1217PubMedCentralPubMedCrossRefGoogle Scholar
  24. Caimano MJ, Drecktrah D, Kung F, Samuels DS (2016) Interaction of the Lyme disease spirochete with its tick vector. Cell Microbiol 18:919–927PubMedCentralPubMedCrossRefGoogle Scholar
  25. Carroll JA, Stewart PE, Rosa P, Elias AF, Garon CF (2003) An enhanced GFP reporter system to monitor gene expression in Borrelia burgdorferi. Microbiology 149:1819–1828CrossRefPubMedGoogle Scholar
  26. Casjens S, Palmer N, van Vugt R, Huang WM, Stevenson B, Rosa P, Lathigra R, Sutton G, Peterson J, Dodson RJ, Haft D, Hickey E, Gwinn M, White O, Fraser CM (2000) A bacterial genome in flux: the twelve linear and nine circular extrachromosomal DNAs in an infectious isolate of the Lyme disease spirochete Borrelia burgdorferi. Mol Microbiol 35:490–516CrossRefPubMedGoogle Scholar
  27. Chaconas G, Norris SJ (2013) Peaceful coexistence amongst Borrelia plasmids: getting by with a little help from their friends? Plasmid 70:161–167PubMedCentralPubMedCrossRefGoogle Scholar
  28. Chaconas G, Stewart PE, Tilly K, Bono JL, Rosa P (2001) Telomere resolution in the Lyme disease spirochete. EMBO J 20:3229–3237PubMedCentralPubMedCrossRefGoogle Scholar
  29. Chan K, Alter L, Barthold SW, Parveen N (2015) Disruption of bbe02 by insertion of a luciferase gene increases transformation efficiency of Borrelia burgdorferi and allows live imaging in Lyme disease susceptible C3H mice. PLoS ONE 10:e0129532PubMedCentralPubMedCrossRefGoogle Scholar
  30. Chan K, Nasereddin T, Alter L, Centurion-Lara A, Giacani L, Parveen N (2016) Treponema pallidum lipoprotein TP0435 expressed in Borrelia burgdorferi produces multiple surface/periplasmic isoforms and mediates adherence. Sci Rep 6:25593PubMedCentralPubMedCrossRefGoogle Scholar
  31. Charon NW, Goldstein SF (2002) Genetics of motility and chemotaxis of a fascinating group of bacteria: the spirochetes. Annu Rev Genet 36:47–73CrossRefPubMedGoogle Scholar
  32. Charon NW, Cockburn A, Li C, Liu J, Miller KA, Miller MR, Motaleb MA, Wolgemuth CW (2012) The unique paradigm of spirochete motility and chemotaxis. Annu Rev Microbiol 66:349–370PubMedCentralPubMedCrossRefGoogle Scholar
  33. Chen Q, Fischer JR, Benoit VM, Dufour NP, Youderian P, Leong JM (2008) In vitro CpG methylation increases the transformation efficiency of Borrelia burgdorferi strains harboring the endogenous linear plasmid lp56. J Bacteriol 190:7885–7891PubMedCentralPubMedCrossRefGoogle Scholar
  34. Chu C-Y, Stewart PE, Bestor A, Hansen B, Lin T, Gao L, Norris SJ, Rosa PA (2016) Function of the Borrelia burgdorferi FtsH homolog is essential for viability both in vitro and in vivo and independent of HflK/C. MBio 7:e00404–16PubMedCentralPubMedGoogle Scholar
  35. Cloud JL, Marconi RT, Eggers CH, Garon CF, Tilly K, Samuels DS (1997) Cloning and expression of the Borrelia burgdorferi lon gene. Gene 194:137–141CrossRefPubMedGoogle Scholar
  36. Coleman JL, Katona LI, Kuhlow C, Toledo A, Okan NA, Tokarz R, Benach JL (2009) Evidence that two ATP-dependent (Lon) proteases in Borrelia burgdorferi serve different functions. PLoS Pathog 5:e1000676PubMedCentralPubMedCrossRefGoogle Scholar
  37. Coutte L, Botkin DJ, Gao L, Norris SJ (2009) Detailed analysis of sequence changes occurring during vlsE antigenic variation in the mouse model of Borrelia burgdorferi infection. PLoS Pathog 5:e1000293PubMedCentralPubMedCrossRefGoogle Scholar
  38. Criswell D, Tobiason VL, Lodmell JS, Samuels DS (2006) Mutations conferring aminoglycoside and spectinomycin resistance in Borrelia burgdorferi. Antimicrob Agents Chemother 50:445–452PubMedCentralPubMedCrossRefGoogle Scholar
  39. Crother TR, Champion CI, Whitelegge JP, Aguilera R, Wu X-Y, Blanco DR, Miller JN, Lovett MA (2004) Temporal analysis of the antigenic composition of Borrelia burgdorferi during infection in rabbit skin. Infect Immun 72:5063–5072PubMedCentralPubMedCrossRefGoogle Scholar
  40. Di L, Pagan PE, Packer D, Martin CL, Akther S, Ramrattan G, Mongodin EF, Fraser CM, Schutzer SE, Luft BJ, Casjens SR, Qiu W-G (2014) BorreliaBase: a phylogeny-centered browser of Borrelia genomes. BMC Bioinf 15:233CrossRefGoogle Scholar
  41. Drecktrah D, Douglas JM, Samuels DS (2010) Use of rpsL as a counterselectable marker in Borrelia burgdorferi. Appl Environ Microbiol 76:985–987CrossRefPubMedGoogle Scholar
  42. Drecktrah D, Hall LS, Hoon-Hanks LL, Samuels DS (2013) An inverted repeat in the ospC operator is required for induction in Borrelia burgdorferi. PLoS ONE 8:e68799PubMedCentralPubMedCrossRefGoogle Scholar
  43. Dresser AR, Hardy PO, Chaconas G (2009) Investigation of the genes involved in antigenic switching at the vlsE locus in Borrelia burgdorferi: an essential role for the RuvAB branch migrase. PLoS Pathog 5:e1000680PubMedCentralPubMedCrossRefGoogle Scholar
  44. Dunham-Ems SM, Caimano MJ, Pal U, Wolgemuth CW, Eggers CH, Balic A, Radolf JD (2009) Live imaging reveals a biphasic mode of dissemination of Borrelia burgdorferi within ticks. J Clin Invest 119:3652–3665PubMedCentralPubMedCrossRefGoogle Scholar
  45. Dunham-Ems SM, Caimano MJ, Eggers CH, Radolf JD (2012) Borrelia burgdorferi requires the alternative sigma factor RpoS for dissemination within the vector during tick-to-mammal transmission. PLoS Pathog 8:e1002532PubMedCentralPubMedCrossRefGoogle Scholar
  46. Dunn JP, Kenedy MR, Iqbal H, Akins DR (2015) Characterization of the β-barrel assembly machine accessory lipoproteins from Borrelia burgdorferi. BMC Microbiol 15:70PubMedCentralPubMedCrossRefGoogle Scholar
  47. Earnhart CG, LeBlanc DV, Alix KE, Desrosiers DC, Radolf JD, Marconi RT (2010) Identification of residues within ligand-binding domain 1 (LBD1) of the Borrelia burgdorferi OspC protein required for function in the mammalian environment. Mol Microbiol 76:393–408PubMedCentralPubMedCrossRefGoogle Scholar
  48. Earnhart CG, Rhodes DV, Marconi RT (2011) Disulfide-mediated oligomer formation in Borrelia burgdorferi outer surface protein C, a critical virulence factor and potential Lyme disease vaccine candidate. Clin Vaccine Immunol 18:901–906PubMedCentralPubMedCrossRefGoogle Scholar
  49. Eggers CH, Kimmel BJ, Bono JL, Elias A, Rosa P, Samuels DS (2001) Transduction by ϕBB-1, a bacteriophage of Borrelia burgdorferi. J Bacteriol 183:4771–4778PubMedCentralPubMedCrossRefGoogle Scholar
  50. Eggers CH, Caimano MJ, Clawson ML, Miller WG, Samuels DS, Radolf JD (2002) Identification of loci critical for replication and compatibility of a Borrelia burgdorferi cp32 plasmid and use of a cp32-based shuttle vector for expression of fluorescent reporters in the Lyme disease spirochaete. Mol Microbiol 43:281–296CrossRefPubMedGoogle Scholar
  51. Eggers CH, Caimano MJ, Radolf JD (2004) Analysis of promoter elements involved in the transcriptional initiation of RpoS-dependent Borrelia burgdorferi genes. J Bacteriol 186:7390–7402PubMedCentralPubMedCrossRefGoogle Scholar
  52. Eggers CH, Caimano MJ, Radolf JD (2006) Sigma factor selectivity in Borrelia burgdorferi: RpoS recognition of the ospE/ospF/elp promoters is dependent on the sequence of the –10 region. Mol Microbiol 59:1859–1875CrossRefPubMedGoogle Scholar
  53. Eggers CH, Gray CM, Preisig AM, Glenn DM, Pereira J, Ayers RW, Alshahrani M, Acabbo C, Becker MR, Bruenn KN, Cheung T, Jendras TM, Shepley AB, Moeller JT (2016) Phage-mediated horizontal gene transfer of both prophage and heterologous DNA by ϕBB-1, a bacteriophage of Borrelia burgdorferi. Pathog Dis 74:ftw107Google Scholar
  54. Elias AF, Stewart PE, Grimm D, Caimano MJ, Eggers CH, Tilly K, Bono JL, Akins DR, Radolf JD, Schwan TG, Rosa P (2002) Clonal polymorphism of Borrelia burgdorferi strain B31 MI: implications for mutagenesis in an infectious strain background. Infect Immun 70:2139–2150PubMedCentralPubMedCrossRefGoogle Scholar
  55. Elias AF, Bono JL, Kupko JJ 3rd, Stewart PE, Krum JG, Rosa PA (2003) New antibiotic resistance cassettes suitable for genetic studies in Borrelia burgdorferi. J Mol Microbiol Biotechnol 6:29–40CrossRefPubMedGoogle Scholar
  56. Ellis TC, Jain S, Linowski AK, Rike K, Bestor A, Rosa PA, Halpern M, Kurhanewicz S, Jewett MW (2014) Correction: In vivo expression technology identifies a novel virulence factor critical for Borrelia burgdorferi persistence in mice. PLoS Pathog 10:e1004260CrossRefPubMedGoogle Scholar
  57. Falkow S (1988) Molecular Koch’s postulates applied to microbial pathogenicity. Rev Infect Dis 10(Suppl 2):S274–276CrossRefPubMedGoogle Scholar
  58. Fine LM, Earnhart CG, Marconi RT (2011) Genetic transformation of the relapsing fever spirochete Borrelia hermsii: stable integration and expression of green fluorescent protein from linear plasmid 200. J Bacteriol 193:3241–3245PubMedCentralPubMedCrossRefGoogle Scholar
  59. Fingerle V, Rauser S, Hammer B, Kahl O, Heimerl C, Schulte-Spechtel U, Gern L, Wilske B (2002) Dynamics of dissemination and outer surface protein expression of different European Borrelia burgdorferi sensu lato strains in artificially infected Ixodes ricinus nymphs. J Clin Microbiol 40:1456–1463PubMedCentralPubMedCrossRefGoogle Scholar
  60. Fingerle V, Goettner G, Gern L, Wilske B, Schulte-Spechtel U (2007) Complementation of a Borrelia afzelii OspC mutant highlights the crucial role of OspC for dissemination of Borrelia afzelii in Ixodes ricinus. Int J Med Microbiol 297:97–107CrossRefPubMedGoogle Scholar
  61. Frank KL, Bundle SF, Kresge ME, Eggers CH, Samuels DS (2003) aadA confers streptomycin-resistance in Borrelia burgdorferi. J Bacteriol 185:6723–6727PubMedCentralPubMedCrossRefGoogle Scholar
  62. Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, Lathigra R, White O, Ketchum KA, Dodson R, Hickey EK, Gwinn M, Dougherty B, Tomb J-F, Fleischmann RD, Richardson D, Peterson J, Kerlavage AR, Quakenbush J, Salzberg S, Hanson M, van Vugt R, Palmer N, Adams MK, Gocayne J, Weidman J, Utterback T, Watthey L, McDonald L, Artiach P, Bowman C, Garland S, Fujii C, Cotton MD, Horst K, Roberts K, Hatch B, Smith HO, Venter JC (1997) Genomic sequence of a Lyme disease spirochete, Borrelia burgdorferi. Nature 390:580–586CrossRefPubMedGoogle Scholar
  63. Galbraith KM, Ng AC, Eggers BJ, Kuchel CR, Eggers CH, Samuels DS (2005) parC mutations in fluoroquinolone-resistant Borrelia burgdorferi. Antimicrob Agents Chemother 49:4354–4357PubMedCentralPubMedCrossRefGoogle Scholar
  64. Ge Y, Old IG, Saint Girons I, Charon NW (1997) Molecular characterization of a large Borrelia burgdorferi motility operon which is initiated by a consensus σ70 promoter. J Bacteriol 179:2289–2299PubMedCentralPubMedCrossRefGoogle Scholar
  65. Gilbert MA, Morton EA, Bundle SF, Samuels DS (2007) Artificial regulation of ospC expression in Borrelia burgdorferi. Mol Microbiol 63:1259–1273CrossRefPubMedGoogle Scholar
  66. Gilmore RD Jr, Piesman J (2000) Inhibition of Borrelia burgdorferi migration from the midgut to the salivary glands following feeding by ticks on OspC-immunized mice. Infect Immun 68:411–414PubMedCentralPubMedCrossRefGoogle Scholar
  67. Grimm D, Eggers CH, Caimano MJ, Tilly K, Stewart PE, Elias AF, Radolf JD, Rosa PA (2004a) Experimental assessment of the roles of linear plasmids lp25 and lp28-1 of Borrelia burgdorferi throughout the infectious cycle. Infect Immun 72:5938–5946PubMedCentralPubMedCrossRefGoogle Scholar
  68. Grimm D, Tilly K, Byram R, Stewart PE, Krum JG, Bueschel DM, Schwan TG, Policastro PF, Elias AF, Rosa PA (2004b) Outer-surface protein C of the Lyme disease spirochete: a protein induced in ticks for infection of mammals. Proc Natl Acad Sci USA 101:3142–3147CrossRefPubMedGoogle Scholar
  69. Grimm D, Tilly K, Bueschel DM, Fisher MA, Policastro PF, Gherardini FC, Schwan TG, Rosa PA (2005) Defining plasmids required by Borrelia burgdorferi for colonization of tick vector Ixodes scapularis (Acari: Ixodidae). J Med Entomol 42:676–684CrossRefPubMedGoogle Scholar
  70. Groshong AM, Blevins JS (2014) Insights into the biology of Borrelia burgdorferi gained through the application of molecular genetics. Adv Appl Microbiol 86:41–143CrossRefPubMedGoogle Scholar
  71. Groshong AM, Gibbons NE, Yang XF, Blevins JS (2012) Rrp2, a prokaryotic enhancer-like binding protein, is essential for viability of Borrelia burgdorferi. J Bacteriol 194:3336–3342PubMedCentralPubMedCrossRefGoogle Scholar
  72. Hayes BM, Jewett MW, Rosa PA (2010) lacZ reporter system for use in Borrelia burgdorferi. Appl Environ Microbiol 76:7407–7412PubMedCentralPubMedCrossRefGoogle Scholar
  73. Hayes BM, Dulebohn DP, Sarkar A, Tilly K, Bestor A, Ambroggio X, Rosa PA (2014) Regulatory protein BBD18 of the Lyme disease spirochete: essential role during tick acquisition? MBio 5:e01017–14PubMedCentralPubMedGoogle Scholar
  74. Hübner A, Yang X, Nolen DM, Popova TG, Cabello FC, Norgard MV (2001) Expression of Borrelia burgdorferi OspC and DbpA is controlled by a RpoN-RpoS regulatory pathway. Proc Natl Acad Sci USA 98:12724–12729CrossRefPubMedGoogle Scholar
  75. Hyde JA, Shaw DK, Smith R III, Trzeciakowski JP, Skare JT (2010) Characterization of a conditional bosR mutant in Borrelia burgdorferi. Infect Immun 78:265–274CrossRefPubMedGoogle Scholar
  76. Hyde JA, Weening EH, Chang M, Trzeciakowski JP, Höök M, Cirillo JD, Skare JT (2011) Bioluminescent imaging of Borrelia burgdorferi in vivo demonstrates that the fibronectin-binding protein BBK32 is required for optimal infectivity. Mol Microbiol 82:99–113PubMedCentralPubMedCrossRefGoogle Scholar
  77. Iqbal H, Kenedy MR, Lybecker M, Akins DR (2016) The TamB ortholog of Borrelia burgdorferi interacts with the β-barrel assembly machine (BAM) complex protein BamA. Mol Microbiol 102:757–774PubMedCentralPubMedCrossRefGoogle Scholar
  78. Jacob F, Monod J (1961) Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol 3:318–356CrossRefPubMedGoogle Scholar
  79. James AE, Rogovskyy AS, Crowley MA, Bankhead T (2016) Characterization of a DNA adenine methyltransferase gene of Borrelia hermsii and its dispensability for murine infection and persistence. PLoS ONE 11:e0155798PubMedCentralPubMedCrossRefGoogle Scholar
  80. Jewett MW, Lawrence K, Bestor AC, Tilly K, Grimm D, Shaw P, VanRaden M, Gherardini F, Rosa PA (2007) The critical role of the linear plasmid lp36 in the infectious cycle of Borrelia burgdorferi. Mol Microbiol 64:1358–1374PubMedCentralPubMedCrossRefGoogle Scholar
  81. Johnson RC (1977) The spirochetes. Annu Rev Microbiol 31:89–106CrossRefPubMedGoogle Scholar
  82. Jutras BL, Bowman A, Brissette CA, Adams CA, Verma A, Chenail AM, Stevenson B (2012a) EbfC (YbaB) is a new type of bacterial nucleoid-associated protein and a global regulator of gene expression in the Lyme disease spirochete. J Bacteriol 194:3395–3406PubMedCentralPubMedCrossRefGoogle Scholar
  83. Jutras BL, Verma A, Adams CA, Brissette CA, Burns LH, Whetstine CR, Bowman A, Chenail AM, Zückert WR, Stevenson B (2012b) BpaB and EbfC DNA-binding proteins regulate production of the Lyme disease spirochete’s infection-associated Erp surface proteins. J Bacteriol 194:778–786PubMedCentralPubMedCrossRefGoogle Scholar
  84. Kao W-CA, Pětrošová H, Ebady R, Lithgow KV, Rojas P, Zhang Y, Kim Y-E, Kim Y-R, Odisho T, Gupta N, Moter A, Cameron CE, Moriarty TJ (2017) Identification of Tp0751 (pallilysin) as a Treponema pallidum vascular adhesin by heterologous expression in the Lyme disease spirochete. Sci Rep 7:1538PubMedCentralPubMedCrossRefGoogle Scholar
  85. Karimi R, Ehrenberg M (1994) Dissociation rate of cognate peptidyl-tRNA from the A-site of hyper-accurate and error-prone ribosomes. Eur J Biochem 226:355–360CrossRefPubMedGoogle Scholar
  86. Karimi R, Ehrenberg M (1996) Dissociation rates of peptidyl-tRNA from the P-site of E. coli ribosomes. EMBO J 15:1149–1154PubMedCentralPubMedCrossRefGoogle Scholar
  87. Kasumba IN, Bestor A, Tilly K, Rosa PA (2015) Use of an endogenous plasmid locus for stable in trans complementation in Borrelia burgdorferi. Appl Environ Microbiol 81:1038–1046PubMedCentralPubMedCrossRefGoogle Scholar
  88. Kawabata H, Norris SJ, Watanabe H (2004) BBE02 disruption mutants of Borrelia burgdorferi B31 have a highly transformable, infectious phenotype. Infect Immun 72:7147–7754PubMedCentralPubMedCrossRefGoogle Scholar
  89. Khajanchi BK, Odeh E, Gao L, Jacobs MB, Philipp MT, Lin T, Norris SJ (2016) Phosphoenolpyruvate phosphotransferase system components modulate gene transcription and virulence of Borrelia burgdorferi. Infect Immun 84:754–764PubMedCentralPubMedCrossRefGoogle Scholar
  90. Knight SW, Samuels DS (1999) Natural synthesis of a DNA-binding protein from the C-terminal domain of DNA gyrase A in Borrelia burgdorferi. EMBO J 18:4875–4881PubMedCentralPubMedCrossRefGoogle Scholar
  91. Knight SW, Kimmel BJ, Eggers CH, Samuels DS (2000) Disruption of the Borrelia burgdorferi gac gene, encoding the naturally synthesized GyrA C-terminal domain. J Bacteriol 182:2048–2051PubMedCentralPubMedCrossRefGoogle Scholar
  92. Krishnavajhala A, Wilder HK, Boyle WK, Damania A, Thornton JA, Pérez de León AA, Teel PD, Lopez JE (2017) Imaging of Borrelia turicatae producing the green fluorescent protein reveals persistent colonization of the Ornithodoros turicata midgut and salivary glands from nymphal acquisition through transmission. Appl Environ Microbiol 83:e02503–16PubMedCentralPubMedCrossRefGoogle Scholar
  93. Kumru OS, Schulze RJ, Slusser JG, Zückert WR (2010) Development and validation of a FACS-based lipoprotein localization screen in the Lyme disease spirochete Borrelia burgdorferi. BMC Microbiol 10:277PubMedCentralPubMedCrossRefGoogle Scholar
  94. Kumru OS, Bunikis I, Sorokina I, Bergström S, Zückert WR (2011a) Specificity and role of the Borrelia burgdorferi CtpA protease in outer membrane protein processing. J Bacteriol 193:5759–5765PubMedCentralPubMedCrossRefGoogle Scholar
  95. Kumru OS, Schulze RJ, Rodnin MV, Ladokhin AS, Zückert WR (2011b) Surface localization determinants of Borrelia OspC/Vsp family lipoproteins. J Bacteriol 193:2814–2825PubMedCentralPubMedCrossRefGoogle Scholar
  96. Kurtti TJ, Munderloh UG, Johnson RC, Ahlstrand GG (1987) Colony formation and morphology in Borrelia burgdorferi. J Clin Microbiol 25:2054–2058PubMedCentralPubMedGoogle Scholar
  97. Labandeira-Rey M, Skare JT (2001) Decreased infectivity in Borrelia burgdorferi strain B31 is associated with loss of linear plasmid 25 or 28-1. Infect Immun 69:446–455PubMedCentralPubMedCrossRefGoogle Scholar
  98. Lawrenz MB, Kawabata H, Purser JE, Norris SJ (2002) Decreased electroporation efficiency in Borrelia burgdorferi containing linear plasmids lp25 and lp56: impact on transformation of infectious B. burgdorferi. Infect Immun 70:4798–4804PubMedCentralPubMedCrossRefGoogle Scholar
  99. Lenhart TR, Akins DR (2010) Borrelia burgdorferi locus BB0795 encodes a BamA orthologue required for growth and efficient localization of outer membrane proteins. Mol Microbiol 75:692–709CrossRefPubMedGoogle Scholar
  100. Lenhart TR, Kenedy MR, Yang X, Pal U, Akins DR (2012) BB0324 and BB0028 are constituents of the Borrelia burgdorferi β-barrel assembly machine (BAM) complex. BMC Microbiol 12:60PubMedCentralPubMedCrossRefGoogle Scholar
  101. Leuba-Garcia S, Martinez R, Gern L (1998) Expression of outer surface proteins A and C of Borrelia afzelii in Ixodes ricinus ticks and in the skin of mice. Zentralbl Bakteriol 287:475–484CrossRefPubMedGoogle Scholar
  102. Liang FT, Jacobs MB, Bowers LC, Philipp MT (2002a) An immune evasion mechanism for spirochetal persistence in Lyme borreliosis. J Exp Med 195:415–422PubMedCentralPubMedCrossRefGoogle Scholar
  103. Liang FT, Nelson FK, Fikrig E (2002b) Molecular adaptation of Borrelia burgdorferi in the murine host. J Exp Med 196:275–280PubMedCentralPubMedCrossRefGoogle Scholar
  104. Liang FT, Yan J, Mbow ML, Sviat SL, Gilmore RD, Mamula M, Fikrig E (2004) Borrelia burgdorferi changes its surface antigenic expression in response to host immune responses. Infect Immun 72:5759–5767PubMedCentralPubMedCrossRefGoogle Scholar
  105. Liang FT, Xu Q, Sikdar R, Xiao Y, Cox JS, Doerrler WT (2010) BB0250 of Borrelia burgdorferi is a conserved and essential inner membrane protein required for cell division. J Bacteriol 192:6105–6115PubMedCentralPubMedCrossRefGoogle Scholar
  106. Lin B, Short SA, Eskildsen M, Klempner MS, Hu LT (2001) Functional testing of putative oligopeptide permease (Opp) proteins of Borrelia burgdorferi: a complementation model in opp- Escherichia coli. Biochim Biophys Acta 1499:222–231CrossRefPubMedGoogle Scholar
  107. Lin T, Gao L, Edmondson DG, Jacobs MB, Philipp MT, Norris SJ (2009) Central role of the Holliday junction helicase RuvAB in vlsE recombination and infectivity of Borrelia burgdorferi. PLoS Pathog 5:e1000679PubMedCentralPubMedCrossRefGoogle Scholar
  108. Lin T, Gao L, Zhang C, Odeh E, Jacobs MB, Coutte L, Chaconas G, Philipp MT, Norris SJ (2012) Analysis of an ordered, comprehensive STM mutant library in infectious Borrelia burgdorferi: insights into the genes required for mouse infectivity. PLoS ONE 7:e47532PubMedCentralPubMedCrossRefGoogle Scholar
  109. Lin T, Troy EB, Hu LT, Gao L, Norris SJ (2014) Transposon mutagenesis as an approach to improved understanding of Borrelia pathogenesis and biology. Front Cell Infect Microbiol 4:63PubMedCentralPubMedCrossRefGoogle Scholar
  110. Lin T, Gao L, Zhao X, Liu J, Norris SJ (2015) Mutations in the Borrelia burgdorferi flagellar type III secretion system genes fliH and fliI profoundly affect spirochete flagellar assembly, morphology, motility, structure, and cell division. MBio 6:e00579–15PubMedCentralPubMedGoogle Scholar
  111. Liu J, Lin T, Botkin DJ, McCrum E, Winkler H, Norris SJ (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 191:5026–5036PubMedCentralPubMedCrossRefGoogle Scholar
  112. Liveris D, Mulay V, Schwartz I (2004) Functional properties of Borrelia burgdorferi recA. J Bacteriol 186:2275–2280PubMedCentralPubMedCrossRefGoogle Scholar
  113. Lybecker MC, Abel CA, Feig AL, Samuels DS (2010) Identification and function of the RNA chaperone Hfq in the Lyme disease spirochete Borrelia burgdorferi. Mol Microbiol 78:622–635PubMedCentralPubMedCrossRefGoogle Scholar
  114. Lybecker MC, Samuels DS (2017) Small RNAs of Borrelia burgdorferi: characterizing functional regulators in a sea of sRNAs. Yale J Biol Med 90:317–323PubMedCentralPubMedGoogle Scholar
  115. Margolis N, Hogan D, Tilly K, Rosa PA (1994) Plasmid location of Borrelia purine biosynthesis gene homologs. J Bacteriol 176:6427–6432PubMedCentralPubMedCrossRefGoogle Scholar
  116. Montgomery RR, Malawista SE, Feen KJ, Bockenstedt LK (1996) Direct demonstration of antigenic substitution of Borrelia burgdorferi ex vivo: exploration of the paradox of the early immune response to outer surface proteins A and C in Lyme disease. J Exp Med 183:261–269CrossRefPubMedGoogle Scholar
  117. Moriarty TJ, Norman MU, Colarusso P, Bankhead T, Kubes P, Chaconas G (2008) Real-time high resolution 3D imaging of the Lyme disease spirochete adhering to and escaping from the vasculature of a living host. PLoS Pathog 4:e1000090PubMedCentralPubMedCrossRefGoogle Scholar
  118. Morozova OV, Dubytska LP, Ivanova LB, Moreno CX, Bryksin AV, Sartakova ML, Dobrikova EY, Godfrey HP, Cabello FC (2005) Genetic and physiological characterization of 23S rRNA and ftsJ mutants of Borrelia burgdorferi isolated by mariner transposition. Gene 357:63–72CrossRefPubMedGoogle Scholar
  119. Nickoloff JA (1995) Electroporation protocols for microorganisms. In Walker JM (ed) Methods in Molecular Biology. Totowa, New Jersey: Humana Press, p 372Google Scholar
  120. Nordstrand A, Barbour AG, Bergström S (2000) Borrelia pathogenesis research in the post-genomic and post-vaccine era. Curr Opin Microbiol 3:86–92CrossRefPubMedGoogle Scholar
  121. Oehler S, Amouyal M, Kolkhof P, von Wilcken-Bergmann B, Müller-Hill B (1994) Quality and position of the three lac operators of E. coli define efficiency of repression. EMBO J 13:3348–3355PubMedCentralPubMedCrossRefGoogle Scholar
  122. Ohnishi J, Piesman J, de Silva AM (2001) Antigenic and genetic heterogeneity of Borrelia burgdorferi populations transmitted by ticks. Proc Natl Acad Sci USA 98:670–675CrossRefPubMedGoogle Scholar
  123. Ouyang Z, Haq S, Norgard MV (2010) Analysis of the dbpBA upstream regulatory region controlled by RpoS in Borrelia burgdorferi. J Bacteriol 192:1965–1974PubMedCentralPubMedCrossRefGoogle Scholar
  124. Ouyang Z, Zhou J, Norgard MV (2014a) Synthesis of RpoS is dependent on a putative enhancer binding protein Rrp2 in Borrelia burgdorferi. PLoS ONE 9:e96917PubMedCentralPubMedCrossRefGoogle Scholar
  125. Ouyang Z, Zhou J, Norgard MV (2014b) CsrA (BB0184) is not involved in activation of the RpoN-RpoS regulatory pathway in Borrelia burgdorferi. Infect Immun 82:1511–1522PubMedCentralPubMedCrossRefGoogle Scholar
  126. Pal U, Yang X, Chen M, Bockenstedt LK, Anderson JF, Flavell RA, Norgard MV, Fikrig E (2004) OspC facilitates Borrelia burgdorferi invasion of Ixodes scapularis salivary glands. J Clin Invest 113:220–230PubMedCentralPubMedCrossRefGoogle Scholar
  127. Picardeau M, Brenot A, Saint Girons I (2001) First evidence for gene replacement in Leptospira spp. Inactivation of L. biflexa flaB results in non-motile mutants deficient in endoflagella. Mol Microbiol 40:189–199CrossRefPubMedGoogle Scholar
  128. Piesman J, Schwan TG (2010) Ecology of borreliae and their arthropod vectors. In Samuels DS, Radolf JD (eds) Borrelia: Molecular biology, host interaction and pathogenesis. Norfolk, UK Caister Academic Press, pp 251–278Google Scholar
  129. Popitsch N, Bilusic I, Rescheneder P, Schroeder R, Lybecker M (2017) Temperature-dependent sRNA transcriptome of the Lyme disease spirochete. BMC Genom 18:28CrossRefGoogle Scholar
  130. Purser JE, Norris SJ (2000) Correlation between plasmid content and infectivity in Borrelia burgdorferi. Proc Natl Acad Sci USA 97:13865–13870CrossRefPubMedGoogle Scholar
  131. Purser JE, Lawrenz MB, Caimano MJ, Howell JK, Radolf JD, Norris SJ (2003) A plasmid-encoded nicotinamidase (PncA) is essential for infectivity of Borrelia burgdorferi in a mammalian host. Mol Microbiol 48:753–764CrossRefPubMedGoogle Scholar
  132. Putteet-Driver AD, Zhong J, Barbour AG (2004) Transgenic expression of RecA of the spirochetes Borrelia burgdorferi and Borrelia hermsii in Escherichia coli revealed differences in DNA repair and recombination phenotypes. J Bacteriol 186:2266–2274PubMedCentralPubMedCrossRefGoogle Scholar
  133. Radolf JD, Caimano MJ, Stevenson B, Hu LT (2012) Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes. Nat Rev Microbiol 10:87–99PubMedCentralPubMedCrossRefGoogle Scholar
  134. Raffel SJ, Battisti JM, Fischer RJ, Schwan TG (2014) Inactivation of genes for antigenic variation in the relapsing fever spirochete Borrelia hermsii reduces infectivity in mice and transmission by ticks. PLoS Pathog 10:e1004056PubMedCentralPubMedCrossRefGoogle Scholar
  135. Ramsey ME, Hyde JA, Medina-Perez DN, Lin T, Gao L, Lundt ME, Li X, Norris SJ, Skare JT, Hu LT (2017) A high-throughput genetic screen identifies previously uncharacterized Borrelia burgdorferi genes important for resistance against reactive oxygen and nitrogen species. PLoS Pathog 13:e1006225PubMedCentralPubMedCrossRefGoogle Scholar
  136. Rathinavelu S, de Silva AM (2001) Purification and characterization of Borrelia burgdorferi from feeding nymphal ticks (Ixodes scapularis). Infect Immun 69:3536–3541PubMedCentralPubMedCrossRefGoogle Scholar
  137. Rego ROM, Bestor A, Rosa PA (2011) Defining the plasmid-borne restriction-modification systems of the Lyme disease spirochete Borrelia burgdorferi. J Bacteriol 193:1161–1171CrossRefPubMedGoogle Scholar
  138. Revel AT, Blevins JS, Almazán C, Neil L, Kocan KM, de la Fuente J, Hagman KE, Norgard MV (2005) bptA (bbe16) is essential for the persistence of the Lyme disease spirochete, Borrelia burgdorferi, in its natural tick vector. Proc Natl Acad Sci USA 102:6972–6977CrossRefPubMedGoogle Scholar
  139. Reyrat J-M, Pelicic V, Gicquel B, Rappuoli R (1998) Counterselectable markers: untapped tools for bacterial genetics and pathogenesis. Infect Immun 66:4011–4017PubMedCentralPubMedGoogle Scholar
  140. Rosa PA, Hogan DM (1992) Colony formation by Borrelia burgdorferi in solid medium: clonal analysis of osp locus variants. In Munderloh UG, Kurtti TJ (eds) First international conference on tick-borne pathogens at the host-vector interface: an agenda for research. St. Paul University of Minnesota, pp 95–103Google Scholar
  141. Rosa PA, Tilly K, Stewart PE (2005) The burgeoning molecular genetics of the Lyme disease spirochaete. Nat Rev Microbiol 3:129–143CrossRefPubMedGoogle Scholar
  142. Samuels DS (1995) Electrotransformation of the spirochete Borrelia burgdorferi. In Nickoloff JA (ed) Electroporation protocols for microorganisms. Totowa, New Jersey Humana Press, pp 253–259Google Scholar
  143. Samuels DS (2006). Antibiotic resistance in Borrelia burgdorferi: applications for genetic manipulation and implications for evolution. In Cabello FC, Hulinska D, Godfrey HP (eds) Molecular biology of spirochetes. Amsterdam, Netherlands IOS Press, pp 56–70Google Scholar
  144. Samuels DS (2011) Gene regulation in Borrelia burgdorferi. Annu Rev Microbiol 65:479–499CrossRefPubMedGoogle Scholar
  145. Samuels DS, Garon CF (1993) Coumermycin A1 inhibits growth and induces relaxation of supercoiled plasmids in Borrelia burgdorferi, the Lyme disease agent. Antimicrob Agents Chemother 37:46–50PubMedCentralPubMedCrossRefGoogle Scholar
  146. Samuels DS, Garon CF (1997) Oligonucleotide-mediated genetic transformation of Borrelia burgdorferi. Microbiology 143:519–522CrossRefPubMedGoogle Scholar
  147. Samuels DS, Mach KE, Garon CF (1994a) Genetic transformation of the Lyme disease agent Borrelia burgdorferi with coumarin-resistant gyrB. J Bacteriol 176:6045–6049PubMedCentralPubMedCrossRefGoogle Scholar
  148. Samuels DS, Radolf JD (2009) Who is the BosR around here anyway? Mol Microbiol 74:1295–1299PubMedCentralPubMedCrossRefGoogle Scholar
  149. Samuels DS, Marconi RT, Huang WM, Garon CF (1994b) gyrB mutations in coumermycin A1-resistant Borrelia burgdorferi. J Bacteriol 176:3072–3075PubMedCentralPubMedCrossRefGoogle Scholar
  150. Sarkar A, Hayes BM, Dulebohn DP, Rosa PA (2011) Regulation of the virulence determinant OspC by bbd18 on linear plasmid lp17 of Borrelia burgdorferi. J Bacteriol 193:5365–5373PubMedCentralPubMedCrossRefGoogle Scholar
  151. Sartakova M, Dobrikova E, Cabello FC (2000) Development of an extrachromosomal cloning vector system for use in Borrelia burgdorferi. Proc Natl Acad Sci USA 97:4850–4855CrossRefPubMedGoogle Scholar
  152. Sartakova ML, Dobrikova EY, Terekhova DA, Devis R, Bugrysheva JV, Morozova OV, Godfrey HP, Cabello FC (2003) Novel antibiotic-resistance markers in pGK12-derived vectors for Borrelia burgdorferi. Gene 303:131–137CrossRefPubMedGoogle Scholar
  153. Schulze RJ, Zückert WR (2006) Borrelia burgdorferi lipoproteins are secreted to the outer surface by default. Mol Microbiol 59:1473–1484CrossRefPubMedGoogle Scholar
  154. Schulze RJ, Chen S, Kumru OS, Zückert WR (2010) Translocation of Borrelia burgdorferi surface lipoprotein OspA through the outer membrane requires an unfolded conformation and can initiate at the C-terminus. Mol Microbiol 76:1266–1278PubMedCentralPubMedCrossRefGoogle Scholar
  155. Schwan TG, 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 38:382–388PubMedCentralPubMedGoogle Scholar
  156. Schwan TG, Piesman J, Golde WT, Dolan MC, Rosa PA (1995) Induction of an outer surface protein on Borrelia burgdorferi during tick feeding. Proc Natl Acad Sci USA 92:2909–2913CrossRefPubMedGoogle Scholar
  157. Seshu J, Esteve-Gassent MD, Labandeira-Rey M, Kim JH, Trzeciakowski JP, Höök M, Skare JT (2006) Inactivation of the fibronectin-binding adhesin gene bbk32 significantly attenuates the infectivity potential of Borrelia burgdorferi. Mol Microbiol 59:1591–1601CrossRefPubMedGoogle Scholar
  158. Shaw DK, Hyde JA, Skare JT (2012) The BB0646 protein demonstrates lipase and haemolytic activity associated with Borrelia burgdorferi, the aetiological agent of Lyme disease. Mol Microbiol 83:319–334CrossRefPubMedGoogle Scholar
  159. Skare JT, Shaw DK, Trzeciakowski JP, Hyde JA (2016) In vivo imaging demonstrates that Borrelia burgdorferi ospC is uniquely expressed temporally and spatially throughout experimental infection. PLoS ONE 11:e0162501PubMedCentralPubMedCrossRefGoogle Scholar
  160. Sohaskey CD, Barbour AG (1999) Esterases in serum-containing growth media counteract chloramphenicol acetyltransferase activity in vitro. Antimicrob Agents Chemother 43:655–660PubMedCentralPubMedGoogle Scholar
  161. Sohaskey CD, Arnold C, Barbour AG (1997) Analysis of promoters in Borrelia burgdorferi by use of a transiently expressed reporter gene. J Bacteriol 179:6837–6842PubMedCentralPubMedCrossRefGoogle Scholar
  162. Sohaskey CD, Zückert WR, Barbour AG (1999) The extended promoters for two outer membrane lipoprotein genes of Borrelia spp. uniquely include a T-rich region. Mol Microbiol 33:41–51CrossRefPubMedGoogle Scholar
  163. Srivastava SY, de Silva AM (2008) Reciprocal expression of ospA and ospC in single cells of Borrelia burgdorferi. J Bacteriol 190:3429–3433PubMedCentralPubMedCrossRefGoogle Scholar
  164. Stevenson B, Bono JL, Elias A, Tilly K, Rosa P (1998) Transformation of the Lyme disease spirochete Borrelia burgdorferi with heterologous DNA. J Bacteriol 180:4850–4855PubMedCentralPubMedGoogle Scholar
  165. Stewart PE, Rosa PA (2008). Transposon mutagenesis of the Lyme disease agent Borrelia burgdorferi. In DeLeo FR, Otto M (eds) Bacterial pathogenesis: methods and protocols. Totowa, New Jersey Humana Press, pp 85–95Google Scholar
  166. Stewart PE, Chaconas G, Rosa P (2003) Conservation of plasmid maintenance functions between linear and circular plasmids in Borrelia burgdorferi. J Bacteriol 185:3202–3209PubMedCentralPubMedCrossRefGoogle Scholar
  167. Stewart P, Thalken R, Bono J, Rosa P (2001) Isolation of a circular plasmid region sufficient for autonomous replication and transformation of infectious Borrelia burgdorferi. Mol Microbiol 39:714–721CrossRefPubMedGoogle Scholar
  168. Stewart PE, Wang X, Bueschel DM, Clifton DR, Grimm D, Tilly K, Carroll JA, Weis JJ, Rosa PA (2006) Delineating the requirement for the Borrelia burgdorferi virulence factor OspC in the mammalian host. Infect Immun 74:3547–3553PubMedCentralPubMedCrossRefGoogle Scholar
  169. Stewart PE, Bestor A, Cullen JN, Rosa PA (2008) A tightly regulated surface protein of Borrelia burgdorferi is not essential to the mouse-tick infectious cycle. Infect Immun 76:1970–1978PubMedCentralPubMedCrossRefGoogle Scholar
  170. Stewart PE, Hoff J, Fischer E, Krum JG, Rosa PA (2004) Genome-wide transposon mutagenesis of Borrelia burgdorferi for identification of phenotypic mutants. Appl Environ Microbiol 70:5973–5979PubMedCentralPubMedCrossRefGoogle Scholar
  171. Stoenner HG, Dodd T, Larsen C (1982) Antigenic variation of Borrelia hermsii. J Exp Med 156:1297–1311CrossRefPubMedGoogle Scholar
  172. Strother KO, de Silva A (2005) Role of Borrelia burgdorferi linear plasmid 25 in infection of Ixodes scapularis ticks. J Bacteriol 187:5776–5781PubMedCentralPubMedCrossRefGoogle Scholar
  173. Terekhova D, Sartakova ML, Wormser GP, Schwartz I, Cabello FC (2002) Erythromycin resistance in Borrelia burgdorferi. Antimicrob Agents Chemother 46:3637–3640PubMedCentralPubMedCrossRefGoogle Scholar
  174. Tilly K, Hauser R, Campbell J, Ostheimer GJ (1993) Isolation of dnaJ, dnaK, and grpE homologues from Borrelia burgdorferi and complementation of Escherichia coli mutants. Mol Microbiol 7:359–369CrossRefPubMedGoogle Scholar
  175. Tilly K, Elias AF, Bono JL, Stewart P, Rosa P (2000) DNA exchange and insertional inactivation in spirochetes. J Mol Microbiol Biotechnol 2:433–442PubMedGoogle Scholar
  176. Tilly K, Elias AF, Errett J, Fischer E, Iyer R, Schwartz I, Bono JL, Rosa P (2001) Genetics and regulation of chitobiose utilization in Borrelia burgdorferi. J Bacteriol 183:5544–5553PubMedCentralPubMedCrossRefGoogle Scholar
  177. Tilly K, Krum JG, Bestor A, Jewett MW, Grimm D, Bueschel D, Byram R, Dorward D, Vanraden MJ, Stewart P, Rosa P (2006) Borrelia burgdorferi OspC protein required exclusively in a crucial early stage of mammalian infection. Infect Immun 74:3554–3564PubMedCentralPubMedCrossRefGoogle Scholar
  178. Tilly K, Checroun C, Rosa PA (2012) Requirements for Borrelia burgdorferi plasmid maintenance. Plasmid 68:1–12PubMedCentralPubMedCrossRefGoogle Scholar
  179. Tilly K, Bestor A, Rosa PA (2013) Lipoprotein succession in Borrelia burgdorferi: similar but distinct roles for OspC and VlsE at different stages of mammalian infection. Mol Microbiol 89:216–227PubMedCentralPubMedCrossRefGoogle Scholar
  180. Troy EB, Lin T, Gao L, Lazinski DW, Camilli A, Norris SJ, Hu LT (2013) Understanding barriers to Borrelia burgdorferi dissemination during infection using massively parallel sequencing. Infect Immun 81:2347–2457PubMedCentralPubMedCrossRefGoogle Scholar
  181. Troy EB, Lin T, Gao L, Lazinski DW, Lundt M, Camilli A, Norris SJ, Hu LT (2016) Global Tn-seq analysis of carbohydrate utilization and vertebrate infectivity of Borrelia burgdorferi. Mol Microbiol 101:1003–1023PubMedCentralPubMedCrossRefGoogle Scholar
  182. Whetstine CR, Slusser JG, Zückert WR (2009) Development of a single-plasmid-based regulatable gene expression system for Borrelia burgdorferi. Appl Environ Microbiol 75:6553–6558PubMedCentralPubMedCrossRefGoogle Scholar
  183. Xu Q, Seemanapalli SV, Lomax L, McShan K, Li X, Fikrig E, Liang FT (2005) Association of linear plasmid 28-1 with an arthritic phenotype of Borrelia burgdorferi. Infect Immun 73:7208–7215PubMedCentralPubMedCrossRefGoogle Scholar
  184. Xu Q, Seemanapalli SV, McShan K, Liang FT (2006) Constitutive expression of outer surface protein C diminishes the ability of Borrelia burgdorferi to evade specific humoral immunity. Infect Immun 74:5177–5184PubMedCentralPubMedCrossRefGoogle Scholar
  185. Xu Q, McShan K, Liang FT (2007) Identification of an ospC operator critical for immune evasion of Borrelia burgdorferi. Mol Microbiol 64:220–231CrossRefPubMedGoogle Scholar
  186. Yang XF, Alani SM, Norgard MV (2003) The response regulator Rrp2 is essential for the expression of major membrane lipoproteins in Borrelia burgdorferi. Proc Natl Acad Sci USA 100:11001–11006CrossRefPubMedGoogle Scholar
  187. Yang XF, Pal U, Alani SM, Fikrig E, Norgard MV (2004) Essential role for OspA/B in the life cycle of the Lyme disease spirochete. J Exp Med 199:641–648PubMedCentralPubMedCrossRefGoogle Scholar
  188. Yang XF, Lybecker MC, Pal U, Alani SM, Blevins J, Revel AT, Samuels DS, Norgard MV (2005) Analysis of the ospC regulatory element controlled by the RpoN-RpoS regulatory pathway in Borrelia burgdorferi. J Bacteriol 187:4822–4829PubMedCentralPubMedCrossRefGoogle Scholar
  189. Ye M, Zhang J-J, Fang X, Lawlis GB, Troxell B, Zhou Y, Gomelsky M, Lou Y, Yang XF (2014) DhhP, a cyclic di-AMP phosphodiesterase of Borrelia burgdorferi, is essential for cell growth and virulence. Infect Immun 82:1840–1849PubMedCentralPubMedCrossRefGoogle Scholar
  190. Zhang J-R, Hardham JM, Barbour AG, Norris SJ (1997) Antigenic variation in Lyme disease borreliae by promiscuous recombination of VMP-like sequence cassettes. Cell 89:275–285CrossRefPubMedGoogle Scholar
  191. Zückert WR, Meyer J (1996) Circular and linear plasmids of Lyme disease spirochetes have extensive homology: characterization of a repeated DNA element. J Bacteriol 178:2287–2298PubMedCentralPubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Division of Biological SciencesUniversity of MontanaMissoulaUSA

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