The past two decades have seen a worldwide resurgence in infections caused by Treponema pallidum subsp. pallidum, the syphilis spirochete. The well-recognized capacity of the syphilis spirochete for early dissemination and immune evasion has earned it the designation 'the stealth pathogen'. Despite the many hurdles to studying syphilis pathogenesis, most notably the inability to culture and to genetically manipulate T. pallidum, in recent years, considerable progress has been made in elucidating the structural, physiological, and regulatory facets of T. pallidum pathogenicity. In this Review, we integrate this eclectic body of information to garner fresh insights into the highly successful parasitic lifestyles of the syphilis spirochete and related pathogenic treponemes.

Department of Biology Faculty of Medicine Masaryk University 625 00 Brno Czech Republic

Department of Medicine UConn Health 263 Farmington Avenue Farmington Connecticut 06030 3715 USA

Department of Microbiology and Immunology Indiana University School of Medicine Indianapolis Indiana 46202 USA

Department of Microbiology The University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas Texas 75390 9048 USA

Departments of Medicine Pediatrics Genetics and Genomic Science Molecular Biology and Biophysics and Immunology UConn Health 263 Farmington Avenue Farmington Connecticut 06030 3715 USA

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Giacani L, Lukehart SA. The endemic treponematoses. Clin Microbiol Rev. 2014;27:89–115. This is a contemporary review of the origins, global epidemiology, and clinical features of the novenereal treponematoses and their continuing threat to worldwide health. PubMed PMC

Sena AC, Pillay A, Cox DL, Radolf JD. In: Manual of Clinical Microbiology. Jorgensen JH, et al., editors. ASM Press; Washington, D.C: 2015. pp. 1055–1081.

Miao R, Fieldsteel AH. Genetics of Treponema: relationship between Treponema pallidum and five cultivable treponemes. J Bacteriol. 1978;133:101–7. PubMed PMC

Miao RM, Fieldsteel AH. Genetic relationship between Treponema pallidum and Treponema pertenue, two noncultivable human pathogens. J Bacteriol. 1980;141:427–9. PubMed PMC

Smajs D, Norris SJ, Weinstock GM. Genetic diversity in Treponema pallidum: implications for pathogenesis, evolution and molecular diagnostics of syphilis and yaws. Infect Genet Evol. 2012;12:191–202. This is a comprehensive review of the genetic and evolutionary relatioships among pathogenic treponemes based on genomic sequencing data. PubMed PMC

Lumeij JT, Mikalova L, Smajs D. Is there a difference between hare syphilis and rabbit syphilis? Cross infection experiments between rabbits and hares. Vet Microbiol. 2013;164:190–4. PubMed

Smajs D, et al. Complete genome sequence of Treponema paraluiscuniculi, strain Cuniculi A: the loss of infectivity to humans is associated with genome decay. PLoS One. 2011;6:e20415. PubMed PMC

Mitja O, et al. Global epidemiology of yaws: a systematic review. Lancet Glob Health. 2015;3:e324–31. PubMed PMC

WHO. Global incidence and prevalence of selected curable sexually transmitted infections-2008. World Health Organization; Geneva: 2012.

Klausner JD. The sound of silence: missing the opportunity to save lives at birth. Bull World Health Organ. 2013;91:158–158A. PubMed PMC

Radolf JD, Tramont EC, Salazar JC. In: Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. Bennett JE, Dolin R, Blaser MJ, editors. Churchill Livingtone Elsevier; Philadelphia: 2014. pp. 2684–2709.

Radolf JD, Hazlett KRO, Lukehart SA. In: Pathogenic Treponema: Cellular and Molecular Biology. Radolf JD, Lukehart SA, editors. Caister Academic Press; Norfolk, UK: 2006. pp. 197–236.

Cameron CE. In: Pathogenic Treponema: Molecular and Cellular Biology. Radolf JD, Lukehart SA, editors. Caister Academic Press; Norwich, UK: 2006. pp. 237–266.

Lafond RE, Lukehart SA. Biological basis for syphilis. Clin Microbiol Rev. 2006;19:29–49. This is a complete, balanced review of the immunology, molecular biology, and pathogenesis of syphilis. PubMed PMC

Izard J, et al. Cryo-electron tomography elucidates the molecular architecture of Treponema pallidum, the syphilis spirochete. J Bacteriol. 2009;191:7566–80. PubMed PMC

Thomas DD, et al. Treponema pallidum invades intercellular junctions of endothelial cell monolayers. Proc Natl Acad Sci U S A. 1988;85:3608–12. PubMed PMC

Wolgemuth CW. Flagellar motility of the pathogenic spirochetes. Semin Cell Dev Biol. 2015;46:104–12. PubMed PMC

Fraser CM, et al. Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science. 1998;281:375–88. This landmark paper is an insightful, beautifully written presentation of the T. pallidum genome, one of the first bacterial genomes to be sequenced. PubMed

Radolf JD, Lukehart SA. In: Pathogenic Treponema: Cellular and Molecular Biology. Radolf JD, Lukehart SA, editors. Caister Academic Press; Norfolk, UK: 2006. pp. 285–322.

Moore MW, et al. Phagocytosis of Borrelia burgdorferi and Treponema pallidum potentiates innate immune activation and induces gamma interferon production. Infect Immun. 2007;75:2046–62. PubMed PMC

Lukehart SA. Scientific monogamy: thirty years dancing with the same bug: 2007 Thomas Parran Award Lecture. Sex Transm Dis. 2008;35:2–7. PubMed

Abell E, Marks R, Jones EW. Secondary syphilis: a clinico-pathological review. Br J Dermatol. 1975;93:53–61. PubMed

van Voorhis WC, Barrett LK, Nasio JM, Plummer FA, Lukehart SA. Lesions of primary and secondary syphilis contain activated cytolytic T cells. Infect Immun. 1996;64:1048–50. PubMed PMC

Salazar JC, et al. Treponema pallidum elicits innate and adaptive cellular immune responses in skin and blood during secondary syphilis: a flow-cytometric analysis. J Infect Dis. 2007;195:879–87. PubMed PMC

Stary G, et al. Host defense mechanisms in secondary syphilitic lesions: a role for IFN-gamma-/IL-17-producing CD8+ T cells? Am J Pathol. 2010;177:2421–32. PubMed PMC

Cruz AR, et al. Immune evasion and recognition of the syphilis spirochete in blood and skin of secondary syphilis patients: two immunologically distinct compartments. PLoS Negl Trop Dis. 2012;6:e1717. PubMed PMC

Cruz AR, et al. Secondary syphilis in Cali, Colombia: new concepts in disease pathogenesis. PLoS Negl Trop Dis. 2010;4:e690. PubMed PMC

Shafii T, Radolf JD, Sanchez PJ, Schulz KF, Murphy FK. In: Sexually Transmitted Diseases. Holmes KK, et al., editors. McGraw Hill; New York: 2008. pp. 1577–1612.

Bishop NH, Miller JN. Humoral immunity in experimental syphilis. I. The demonstration of resistance conferred by passive immunization. J Immunol. 1976;117:191–6. PubMed

Perine PL, Weiser RS, Klebanoff SJ. Immunity to syphilis. I. Passive transfer in rabbits with hyperimmune serum. Infect Immun. 1973;8:787–90. PubMed PMC

Sell S, Norris SJ. The biology, pathology, and immunology of syphilis. Int Rev Exp Pathol. 1983;24:203–76. PubMed

Sell S, Salman J, Norris SJ. Reinfection of chancre-immune rabbits with Treponema pallidum. I. Light and immunofluorescence studies. Am J Pathol. 1985;118:248–55. PubMed PMC

Salazar JC, Hazlett KR, Radolf JD. The immune response to infection with Treponema pallidum, the stealth pathogen. Microbes Infect. 2002;4:1133–40. PubMed

Ho EL, Lukehart SA. Syphilis: using modern approaches to understand an old disease. J Clin Invest. 2011;121:4584–92. This well written article presents a state-of-the-art summary of the global molecular epidemiology and pathogenesis of syphilis. PubMed PMC

Norris SJ, Cox DL, Weinstock GM. Biology of Treponema pallidum: correlation of functional activities with genome sequence data. J Mol Microbiol Biotechnol. 2001;3:37–62. PubMed

Nelson RA., Jr Factors affecting the survival of Treponema pallidum in vitro. Am J Hyg. 1948;48:120–32. PubMed

Fieldsteel AH, Cox DL, Moeckli RA. Cultivation of virulent Treponema pallidum in tissue culture. Infect Immun. 1981;32:908–15. PubMed PMC

Norris SJ. In vitro cultivation of Treponema pallidum: independent confirmation. Infect Immun. 1982;36:437–9. PubMed PMC

Norris SJ, Edmondson DG. Factors affecting the multiplication and subculture of Treponema pallidum subsp. pallidum in a tissue culture system. Infect Immun. 1986;53:534–9. PubMed PMC

Naqvi AA, Shahbaaz M, Ahmad F, Hassan MI. Identification of functional candidates amongst hypothetical proteins of Treponema pallidum ssp. pallidum. PLoS One. 2015;10:e0124177. PubMed PMC

Deka RK, Brautigam CA, Biddy BA, Liu WZ, Norgard MV. Evidence for an ABC-type riboflavin transporter system in pathogenic spirochetes. MBio. 2013;4:e00615–12. PubMed PMC

Deka RK, Brautigam CA, Liu WZ, Tomchick DR, Norgard MV. Evidence for posttranslational protein flavinylation in the syphilis spirochete Treponema pallidum: structural and biochemical insights from the catalytic core of a periplasmic flavin-trafficking protein. MBio. 2015;6 This report presents a biochemical/molecular analysis of a unique periplasmic flavin utilization pathway in T. pallidum and describes the spirochete's Rnf system for generating an electrochemical gradient across the cytoplasmic membrane. PubMed PMC

Lukehart SA, Marra CM. Isolation and laboratory maintenance of Treponema pallidum. Curr Protoc Microbiol. 2007;Chapter 12(Unit 12A):1. PubMed

Alderete JF, Baseman JB. Surface-associated host proteins on virulent Treponema pallidum. Infect Immun. 1979;26:1048–56. PubMed PMC

Radolf JD. Treponema pallidum and the quest for outer membrane proteins. Mol Microbiol. 1995;16:1067–73. PubMed

Silver AC, et al. MyD88 deficiency markedly worsens tissue inflammation and bacterial clearance in mice infected with Treponema pallidum, the agent of syphilis. PLoS One. 2013;8:e71388. PubMed PMC

Cameron CE, Lukehart SA. Current status of syphilis vaccine development: need, challenges, prospects. Vaccine. 2014;32:1602–9. PubMed PMC

Norris SJ, Weinstock GM. In: Pathogenic Treponema: Molecular and Cellular Biology. Radolf JD, Lukehart SA, editors. Norwich, U.K: 2006. pp. 19–38.

Radolf JD, Norgard MV, Schulz WW. Outer membrane ultrastructure explains the limited antigenicity of virulent Treponema pallidum. Proc Natl Acad Sci U S A. 1989;86:2051–5. This report describes the discovery of rare outer membrane proteins in T. pallidum by freeze-fracture electron microscopy. PubMed PMC

Walker EM, Zampighi GA, Blanco DR, Miller JN, Lovett MA. Demonstration of rare protein in the outer membrane of Treponema pallidum subsp. pallidum by freeze-fracture analysis. J Bacteriol. 1989;171:5005–11. PubMed PMC

Magnuson HJ, Eagle H, Fleischman R. The minimal infectious inoculum of Spirochaeta pallida (Nichols strain) and a consideration of its rate of multiplication in vivo. Am J Syph Gonorrhea Vener Dis. 1948;32:1–18. PubMed

Centurion-Lara A, et al. Treponema pallidum major sheath protein homologue Tpr K is a target of opsonic antibody and the protective immune response. J Exp Med. 1999;189:647–56. PubMed PMC

Gray RR, et al. Molecular evolution of the tprC, D, I, K, G, and J genes in the pathogenic genus Treponema. Mol Biol Evol. 2006;23:2220–33. PubMed

Ellen RP. In: Pathogenic Treponema: Molecular and Cellular Biology. Radolf JD, Lukehart SA, editors. Caister Academic Press; Norwich, UK: 2006. pp. 357–386.

Deitsch KW, Lukehart SA, Stringer JR. Common strategies for antigenic variation by bacterial, fungal and protozoan pathogens. Nat Rev Microbiol. 2009;7:493–503. This review describes antigenic variation by T. pallidum in the context of well characterized mechanisms for varying surface antigenicity in other pathogens. PubMed PMC

Hazlett KR, et al. The TprK protein of Treponema pallidum is periplasmic and is not a target of opsonic antibody or protective immunity. J Exp Med. 2001;193:1015–26. PubMed PMC

Cox DL, et al. Surface immunolabeling and consensus computational framework to identify candidate rare outer membrane proteins of Treponema pallidum. Infect Immun. 2010;78:5178–94. PubMed PMC

Cameron CE, et al. Opsonic potential, protective capacity, and sequence conservation of the Treponema pallidum subspecies pallidum Tp92. J Infect Dis. 2000;181:1401–13. PubMed

Anand A, et al. Bipartite topology of Treponema pallidum repeat proteins C/D and I: outer membrane insertion, trimerization, and porin function require a C-terminal β-barrel domain. J Biol Chem. 2015;290:12313–31. This report describes the use of molecular, biophysical, and immunological methodologies to establish the bipartite topology of Tpr outer membrane proteins. PubMed PMC

Anand A, et al. TprC/D (Tp0117/131), a trimeric, pore-forming rare outer membrane protein of Treponema pallidum, has a bipartite domain structure. J Bacteriol. 2012;194:2321–33. PubMed PMC

Anand A, et al. The major outer sheath protein (Msp) of Treponema denticola has a bipartite domain architecture and exists as periplasmic and outer membrane-spanning conformers. J Bacteriol. 2013 PubMed PMC

Nikaido H. Molecular basis of bacterial outer membrane permeability revisited. Microbiol Mol Biol Rev. 2003;67:593–656. PubMed PMC

Centurion-Lara A, et al. Fine analysis of genetic diversity of the tpr gene family among treponemal species, subspecies and strains. PLoS Negl Trop Dis. 2013;7:e2222. PubMed PMC

Desrosiers DC, et al. TP0326, a Treponema pallidum beta-barrel assembly machinery A (BamA) orthologue and rare outer membrane protein. Mol Microbiol. 2011;80:1496–515. PubMed PMC

Luthra A, et al. A homology model reveals novel structural features and an immunodominant surface loop/opsonic target in the Treponema pallidum BamA ortholog TP_0326. J Bacteriol. 2015;197:1906–20. PubMed PMC

Selkrig J, Leyton DL, Webb CT, Lithgow T. Assembly of β-barrel proteins into bacterial outer membranes. Biochim Biophys Acta. 2014;1843:1542–50. PubMed

Noinaj N, et al. Structural insight into the biogenesis of β-barrel membrane proteins. Nature. 2013;501:385–90. PubMed PMC

Fitzgerald TJ, Johnson RC, Miller JN, Sykes JA. Characterization of the attachment of Treponema pallidum (Nichols strain) to cultured mammalian cells and the potential relationship of attachment to pathogenicity. Infect Immun. 1977;18:467–78. PubMed PMC

Hayes NS, Muse KE, Collier AM, Baseman JB. Parasitism by virulent Treponema pallidum of host cell surfaces. Infect Immun. 1977;17:174–86. PubMed PMC

Fitzgerald TJ, Repesh LA, Blanco DR, Miller JN. Attachment of Treponema pallidum to fibronectin, laminin, collagen IV, and collagen I, and blockage of attachment by immune rabbit IgG. Br J Vener Dis. 1984;60:357–63. PubMed PMC

Cameron CE, Brown EL, Kuroiwa JM, Schnapp LM, Brouwer NL. Treponema pallidum fibronectin-binding proteins. J Bacteriol. 2004;186:7019–22. PubMed PMC

Cameron CE. Identification of a Treponema pallidum laminin-binding protein. Infect Immun. 2003;71:2525–33. PubMed PMC

Cameron CE, Brouwer NL, Tisch LM, Kuroiwa JM. Defining the interaction of the Treponema pallidum adhesin Tp0751 with laminin. Infect Immun. 2005;73:7485–94. PubMed PMC

Houston S, Hof R, Honeyman L, Hassler J, Cameron CE. Activation and proteolytic activity of the Treponema pallidum metalloprotease, pallilysin. PLoS Pathog. 2012;8:e1002822. This report describes a biochemical/molecular characterization of TP0751 (pallilysin) as a zinc-dependent proteinase capable of degrading fibrin clots in addition to its role as a laminin-binding adhesin. PubMed PMC

Houston S, et al. The multifunctional role of the pallilysin-associated Treponema pallidum protein, Tp0750, in promoting fibrinolysis and extracellular matrix component degradation. Mol Microbiol. 2014;91:618–34. PubMed PMC

Brinkman MB, et al. A novel Treponema pallidum antigen, TP0136, is an outer membrane protein that binds human fibronectin. Infect Immun. 2008;76:1848–57. PubMed PMC

Ke W, Molini BJ, Lukehart SA, Giacani L. Treponema pallidum subsp. pallidum TP0136 protein is heterogeneous among isolates and binds cellular and plasma fibronectin via its NH2-terminal end. PLoS Negl Trop Dis. 2015;9:e0003662. PubMed PMC

Chan K, et al. Treponema pallidum lipoprotein TP0435 expressed in Borrelia burgdorferi produces multiple surface/periplasmic isoforms and mediates adherence. Sci Rep. 2016;6:25593. This is a ground breaking report in its use of Borrelia burgdorferi as a genetic surrogate for T. pallidum to characterize potential adhesins and surface antigenic targets. PubMed PMC

Penn CW, Cockayne A, Bailey MJ. The outer membrane of Treponema pallidum: biological significance and biochemical properties. J Gen Microbiol. 1985;131:2349–57. PubMed

Cox DL, Chang P, McDowall AW, Radolf JD. The outer membrane, not a coat of host proteins, limits antigenicity of virulent Treponema pallidum. Infect Immun. 1992;60:1076–83. PubMed PMC

Lukehart SA, Shaffer JM, Baker-Zander SA. A subpopulation of Treponema pallidum is resistant to phagocytosis: possible mechanism of persistence. J Infect Dis. 1992;166:1449–53. PubMed

Centurion-Lara A, et al. Gene conversion: a mechanism for generation of heterogeneity in the tprK gene of Treponema pallidum during infection. Mol Microbiol. 2004;52:1579–96. PubMed

LaFond RE, Molini BJ, Van Voorhis WC, Lukehart SA. Antigenic variation of TprK V regions abrogates specific antibody binding in syphilis. Infect Immun. 2006;74:6244–51. PubMed PMC

Giacani L, et al. Antigenic variation in Treponema pallidum: TprK sequence diversity accumulates in response to immune pressure during experimental syphilis. J Immunol. 2010;184:3822–9. PubMed PMC

Reid TB, Molini BJ, Fernandez MC, Lukehart SA. Antigenic variation of TprK facilitates development of secondary syphilis. Infect Immun. 2014;82:4959–67. PubMed PMC

Giacani L, et al. Comparative investigation of the genomic regions involved in antigenic variation of the TprK antigen among treponemal species, subspecies, and strains. J Bacteriol. 2012;194:4208–25. PubMed PMC

Petrosova H, et al. Resequencing of Treponema pallidum ssp. pallidum strains Nichols and SS14: correction of sequencing errors resulted in increased separation of syphilis treponeme subclusters. PLoS One. 2013;8:e74319. PubMed PMC

Giacani L, Lukehart S, Centurion-Lara A. Length of guanosine homopolymeric repeats modulates promoter activity of subfamily II tpr genes of Treponema pallidum ssp. pallidum. FEMS Immunol Med Microbiol. 2007;51:289–301. PubMed PMC

Silhavy TJ, Kahne D, Walker S. The bacterial cell envelope. Cold Spring Harb Perspect Biol. 2010;2:a000414. PubMed PMC

Hovind-Hougen K. In: Pathogenesis and Immunology of Treponemal Infection. Schell RF, Musher DM, editors. Marcel Dekker; New York: 1983. pp. 3–28.

Liu J, et al. Cellular architecture of Treponema pallidum: novel flagellum, periplasmic cone, and cell envelope as revealed by cryo electron tomography. J Mol Biol. 2010;403:546–61. A materful use of cryoelectron microscopy and scanning probe microscopy to describe the native ultrastructure of T. pallidum. PubMed PMC

Briegel A, et al. New insights into bacterial chemoreceptor array structure and assembly from electron cryotomography. Biochemistry. 2014;53:1575–85. PubMed PMC

Deka RK, Goldberg MS, Hagman KE, Norgard MV. The Tp38 (TpMglB-2) lipoprotein binds glucose in a manner consistent with receptor function in Treponema pallidum. J Bacteriol. 2004;186:2303–8. PubMed PMC

Deka RK, et al. Structural evidence that the 32-kilodalton lipoprotein (Tp32) of Treponema pallidum is an L-methionine-binding protein. J Biol Chem. 2004;279:55644–50. PubMed

Bian J, Tu Y, Wang SM, Wang XY, Li C. Evidence that TP_0144 of Treponema pallidum is a thiamine-binding protein. J Bacteriol. 2015;197:1164–72. PubMed PMC

Jaehme M, Slotboom DJ. Diversity of membrane transport proteins for vitamins in bacteria and archaea. Biochim Biophys Acta. 2015;1850:565–76. PubMed

Lee YH, Deka RK, Norgard MV, Radolf JD, Hasemann CA. Treponema pallidum TroA is a periplasmic zinc-binding protein with a helical backbone. Nat Struct Biol. 1999;6:628–33. PubMed

Deka RK, et al. The PnrA (Tp0319; TmpC) lipoprotein represents a new family of bacterial purine nucleoside receptor encoded within an ATP-binding cassette (ABC)-like operon in Treponema pallidum. J Biol Chem. 2006;281:8072–81. PubMed

Machius M, et al. Structural and biochemical basis for polyamine binding to the Tp0655 lipoprotein of Treponema pallidum: putative role for Tp0655 (TpPotD) as a polyamine receptor. J Mol Biol. 2007;373:681–94. PubMed PMC

Deka RK, Brautigam CA, Liu WZ, Tomchick DR, Norgard MV. The TP0796 lipoprotein of Treponema pallidum is a bimetal-dependent FAD pyrophosphatase with a potential role in flavin homeostasis. J Biol Chem. 2013;288:11106–21. PubMed PMC

Brautigam CA, Deka RK, Schuck P, Tomchick DR, Norgard MV. Structural and thermodynamic characterization of the interaction between two periplasmic Treponema pallidum lipoproteins that are components of a TPR-protein-associated TRAP transporter (TPAT) J Mol Biol. 2012;420:70–86. An extraordinary biochemical and structural analysis of a unique transporter in T. pallidum. PubMed PMC

Deka RK, et al. Structural, bioinformatic, and in vivo analyses of two Treponema pallidum lipoproteins reveal a unique TRAP transporter. J Mol Biol. 2012;416:678–96. PubMed PMC

Austin FE, Cox CD. Lactate oxidation by Treponema pallidum. Current Microbiology. 1986;13:123–128.

Fraser CM, et al. Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature. 1997;390:580–6. PubMed

Gorke B, Stulke J. Carbon catabolite repression in bacteria: many ways to make the most out of nutrients. Nat Rev Microbiol. 2008;6:613–24. PubMed

Norris SJ, Fraser CM, Weinstock GM. Illuminating the agent of syphilis: the Treponema pallidum genome project. Electrophoresis. 1998;19:551–3. PubMed

Roberson RS, Ronimus RS, Gephard S, Morgan HW. Biochemical characterization of an active pyrophosphate-dependent phosphofructokinase from Treponema pallidum. FEMS Microbiol Lett. 2001;194:257–60. PubMed

Moore SA, Ronimus RS, Roberson RS, Morgan HW. The structure of a pyrophosphate-dependent phosphofructokinase from the Lyme disease spirochete Borrelia burgdorferi. Structure. 2002;10:659–71. PubMed

Fothergill-Gilmore LA, Michels PA. Evolution of glycolysis. Prog Biophys Mol Biol. 1993;59:105–235. PubMed

Mertens E. ATP versus pyrophosphate: glycolysis revisited in parasitic protists. Parasitol Today. 1993;9:122–6. PubMed

Higuchi M, Yamamoto Y, Kamio Y. Molecular biology of oxygen tolerance in lactic acid bacteria: Functions of NADH oxidases and Dpr in oxidative stress. J Biosci Bioeng. 2000;90:484–93. PubMed

Baker JL, Derr AD, Faustoferri RC, Quivey RG., Jr Loss of NADH oxidase activity in Streptococcus mutans leads to Rex-mediated overcompensation of NAD+ regeneration by lactate dehydrogenase. J Bacteriol. 2015 PubMed PMC

Cox DL, et al. Effects of molecular oxygen, oxidation-reduction potential, and antioxidants upon in vitro replication of Treponema pallidum subsp. pallidum. Appl Environ Microbiol. 1990;56:3063–72. PubMed PMC

Meyron-Holtz EG, Ghosh MC, Rouault TA. Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo. Science. 2004;306:2087–90. PubMed

Mayer F, Muller V. Adaptations of anaerobic archaea to life under extreme energy limitation. FEMS Microbiol Rev. 2014;38:449–72. PubMed

Hazlett KR, et al. The Treponema pallidum tro operon encodes a multiple metal transporter, a zinc-dependent transcriptional repressor, and a semi-autonomously expressed phosphoglycerate mutase. J Biol Chem. 2003;278:20687–94. PubMed

Gherardini FC, Boylan JA, Brett PJ. In: Pathogenic Treponema: Molecular and Cellular Biology. Radolf JD, Lukehart SA, editors. Caister Academic Press; Norwich, UK: 2006. pp. 101–126.

Alderete JF, Peterson KM, Baseman JB. Affinities of Treponema pallidum for human lactoferrin and transferrin. Genitourin Med. 1988;64:359–63. PubMed PMC

Deka RK, et al. Crystal structure of the Tp34 (TP0971) lipoprotein of Treponema pallidum: implications of its metal-bound state and affinity for human lactoferrin. J Biol Chem. 2007;282:5944–58. PubMed

Noinaj N, et al. Structural basis for iron piracy by pathogenic Neisseria. Nature. 2012;483:53–8. PubMed PMC

Ward DM, Kaplan J. Ferroportin-mediated iron transport: expression and regulation. Biochim Biophys Acta. 2012;1823:1426–33. PubMed PMC

Desrosiers DC, et al. The general transition metal (Tro) and Zn2+ (Znu) transporters in Treponema pallidum: analysis of metal specificities and expression profiles. Mol Microbiol. 2007;65:137–52. PubMed

Brautigam CA, et al. Biophysical and bioinformatic analyses implicate the Treponema pallidum Tp34 lipoprotein (Tp0971) in transition metal homeostasis. J Bacteriol. 2012;194:6771–81. PubMed PMC

Koch D, et al. Characterization of a dipartite iron uptake system from uropathogenic Escherichia coli strain F11. J Biol Chem. 2011;286:25317–30. PubMed PMC

Posey JE, Hardham JM, Norris SJ, Gherardini FC. Characterization of a manganese-dependent regulatory protein, TroR, from Treponema pallidum. Proc Natl Acad Sci U S A. 1999;96:10887–92. This report describes the first molecular analysis of a transcriptional factor in T. pallidum. PubMed PMC

Hazlett KR, et al. Contribution of neelaredoxin to oxygen tolerance by Treponema pallidum. Methods Enzymol. 2002;353:140–56. PubMed

Jenney FE, Jr, Verhagen MF, Cui X, Adams MW. Anaerobic microbes: oxygen detoxification without superoxide dismutase. Science. 1999;286:306–9. PubMed

Imlay JA. Cellular defenses against superoxide and hydrogen peroxide. Annu Rev Biochem. 2008;77:755–76. PubMed PMC

Thumiger A, et al. Crystal structure of antigen TpF1 from Treponema pallidum. Proteins. 2006;62:827–30. PubMed

Parsonage D, et al. Broad specificity AhpC-like peroxiredoxin and its thioredoxin reductant in the sparse antioxidant defense system of Treponema pallidum. Proc Natl Acad Sci U S A. 2010;107:6240–5. This report presents a detailed biochemical analysis of T. pallidum's unique, robust enzymatic defense against peroxide stress. PubMed PMC

Radolf JD, Borenstein LA, Kim JY, Fehniger TE, Lovett MA. Role of disulfide bonds in the oligomeric structure and protease resistance of recombinant and native Treponema pallidum surface antigen 4D. J Bacteriol. 1987;169:1365–71. PubMed PMC

Brautigam CA, Deka RK, Liu WZ, Norgard MV. Insights into the potential function and membrane organization of the TP0435 (Tp17) lipoprotein from Treponema pallidum derived from structural and biophysical analyses. Protein Sci. 2015;24:11–9. PubMed PMC

Casino P, Rubio V, Marina A. The mechanism of signal transduction by two-component systems. Curr Opin Struct Biol. 2010;20:763–71. PubMed

Anderson JK, Smith TG, Hoover TR. Sense and sensibility: flagellum-mediated gene regulation. Trends Microbiol. 2010;18:30–7. PubMed PMC

Stamm LV, Gherardini FC, Parrish EA, Moomaw CR. Heat shock response of spirochetes. Infect Immun. 1991;59:1572–5. PubMed PMC

Romling U, Galperin MY, Gomelsky M. Cyclic di-GMP: the first 25 years of a universal bacterial second messenger. Microbiol Mol Biol Rev. 2013;77:1–52. PubMed PMC

Guo MS, Gross CA. Stress-induced remodeling of the bacterial proteome. Curr Biol. 2014;24:R424–34. PubMed PMC

Giacani L, Denisenko O, Tompa M, Centurion-Lara A. Identification of the Treponema pallidum subsp. pallidum TP0092 (RpoE) regulon and its implications for pathogen persistence in the host and syphilis pathogenesis. J Bacteriol. 2013;195:896–907. This is the only report to use chromatin immunoprecipitation to define the cohort of genes controlled by an alternative sigma factor in T. pallidum. PubMed PMC

Studholme DJ, Buck M. The biology of enhancer-dependent transcriptional regulation in bacteria: insights from genome sequences. FEMS Microbiol Lett. 2000;186:1–9. PubMed

Bush M, Dixon R. The role of bacterial enhancer binding proteins as specialized activators of σ54-dependent transcription. Microbiol Mol Biol Rev. 2012;76:497–529. PubMed PMC

Hubner A, et al. Expression of Borrelia burgdorferi OspC and DbpA is controlled by a RpoN-RpoS regulatory pathway. Proc Natl Acad Sci U S A. 2001;98:12724–9. PubMed PMC

Yang XF, Alani SM, Norgard MV. The response regulator Rrp2 is essential for the expression of major membrane lipoproteins in Borrelia burgdorferi. Proc Natl Acad Sci U S A. 2003;100:11001–6. PubMed PMC

Cejkova D, et al. Whole genome sequences of three Treponema pallidum ssp. pertenue strains: yaws and syphilis treponemes differ in less than 0.2% of the genome sequence. PLoS Negl Trop Dis. 2012;6:e1471. PubMed PMC

Staudova B, et al. Whole genome sequence of the Treponema pallidum subsp. endemicum strain Bosnia A: the genome is related to yaws treponemes but contains few loci similar to syphilis treponemes. PLoS Negl Trop Dis. 2014;8:e3261. PubMed PMC

Giacani L, et al. Complete genome sequence of the Treponema pallidum subsp. pallidum Sea81–4 strain. Genome Announc. 2014;2 PubMed PMC

Petrosova H, et al. Whole genome sequence of Treponema pallidum ssp. pallidum, strain Mexico A, suggests recombination between yaws and syphilis strains. PLoS Negl Trop Dis. 2012;6:e1832. PubMed PMC

Peterkofsky A, Wang G, Seok YJ. Parallel PTS systems. Arch Biochem Biophys. 2006;453:101–7. PubMed

Pfluger-Grau K, Gorke B. Regulatory roles of the bacterial nitrogen-related phosphotransferase system. Trends Microbiol. 2010;18:205–14. PubMed

Reizer J, Novotny MJ, Hengstenberg W, Saier MH., Jr Properties of ATP-dependent protein kinase from Streptococcus pyogenes that phosphorylates a seryl residue in HPr, a phosphocarrier protein of the phosphotransferase system. J Bacteriol. 1984;160:333–40. PubMed PMC

Deutscher J, Kessler U, Hengstenberg W. Streptococcal phosphoenolpyruvate: sugar phosphotransferase system: purification and characterization of a phosphoprotein phosphatase which hydrolyzes the phosphoryl bond in seryl-phosphorylated histidine-containing protein. J Bacteriol. 1985;163:1203–9. PubMed PMC

Gonzalez CF, Stonestrom AJ, Lorca GL, Saier MH., Jr Biochemical characterization of phosphoryl transfer involving HPr of the phosphoenolpyruvate-dependent phosphotransferase system in Treponema denticola, an organism that lacks PTS permeases. Biochemistry. 2005;44:598–608. PubMed

Lee CR, Cho SH, Yoon MJ, Peterkofsky A, Seok YJ. Escherichia coli enzyme IIANtr regulates the K+ transporter TrkA. Proc Natl Acad Sci U S A. 2007;104:4124–9. PubMed PMC

Deutscher J, et al. The bacterial phosphoenolpyruvate:carbohydrate phosphotransferase system: regulation by protein phosphorylation and phosphorylation-dependent protein-protein interactions. Microbiol Mol Biol Rev. 2014;78:231–56. PubMed PMC

McDonough KA, Rodriguez A. The myriad roles of cyclic AMP in microbial pathogens: from signal to sword. Nat Rev Microbiol. 2012;10:27–38. PubMed PMC

Radolf JD, Bourell KW, Akins DR, Brusca JS, Norgard MV. Analysis of Borrelia burgdorferi membrane architecture by freeze-fracture electron microscopy. J Bacteriol. 1994;176:21–31. PubMed PMC

Luthra A, et al. The transition from closed to open conformation of Treponema pallidum outer membrane-associated lipoprotein TP0453 involves membrane sensing and integration by two amphipathic helices. J Biol Chem. 2011;286:41656–68. PubMed PMC

McKevitt M, et al. Genome scale identification of Treponema pallidum antigens. Infect Immun. 2005;73:4445–50. PubMed PMC

Brinkman MB, et al. Reactivity of antibodies from syphilis patients to a protein array representing the Treponema pallidum proteome. J Clin Microbiol. 2006;44:888–91. PubMed PMC

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