More than a century after the discovery of Treponema pallidum (Tp), syphilis remains a major threat to global public health. Our limited understanding of this sexually transmitted disease reflects the many peculiarities of its etiologic agent, most notably an inability to replicate in vitro, a labile outer membrane (OM), and an extremely narrow host range. We showed during prior funding intervals that the molecular architecture of Tp differs radically from that of Gram-negative bacteria. The spirochete's highly unusual OM is the ultrastructural basis for its designation as the stealth pathogen and the prime determinant of its capacity to evade innate and adaptive immune responses. The experimental data derived from our in silico mining of the Tp genome during the current funding interval have yielded compelling evidence that the particles visualized in the Tp OM by freeze-fracture EM more than 20 years ago are integral OMPs and canonical -barrels. Three developments now enable us to carry this work forward to an integrated structural, functional, and immunological investigation of Tp rare OMPs. One is the characterization of TP0326/BamA, an ortholog for the central component of the molecular machine that chaperones precursor OMPs from the periplasm into the OM. Because of its potential to illuminate both the biogenesis and composition of the Tp OM, we liken TP0326 to the treponemal equivalent of the Rosetta Stone. The second is the demonstration that TprC/D is a trimeric, channel-forming protein and functional E. coli OmpF ortholog. We now hypothesize that the molecule's bipartite domain structure represents a potential topological-functional paradigm for other members of the Tpr family. The third is the generation of a robust list of candidate OMPs that, when more fully investigated, will yield a comprehensive picture of the surface weaponry Tp deploy to establish and maintain persistent infection. Our long-term objective is to continue to refine our model for the molecular architecture of the Tp cell envelope as a conceptual framework for elucidating the complex and shifting balance between pathogen and host that characterizes human syphilis. We have formulated Specific Aims to maintain our momentum towards this overarching goal: (i) further characterization of TP0326/BamA; (ii) further characterization of TprC and its closely related Tpr family members, TprI and TprF; and (iii) using our roster of candidate OMPs to expand our knowledge of Tp's OMP repertoire and the contributions of novel OMPs to host-pathogen interactions during syphilitic infection.

Public Health Relevance

Syphilis is a chronic sexually transmitted disease caused by the noncultivatable spirochete Treponema pallidum (Tp). In a number of previously published studies, we have demonstrated that the outer membrane (OM) of Tp differs markedly from those of Gram-negative bacteria, such as Escherichia coli, most notably with respect to its paucity of integral membrane proteins. The experiments in this proposal will identify the repertoire of surface-exposed OM proteins Tp uses to establish and maintain persistent infection in its obligate human host.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacterial Pathogenesis Study Section (BACP)
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Vincent, Leah Rebecca
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University of Connecticut
Internal Medicine/Medicine
Schools of Medicine
United States
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Radolf, Justin D; Kumar, Sanjiv (2018) The Treponema pallidum Outer Membrane. Curr Top Microbiol Immunol 415:1-38
Kumar, Sanjiv; Caimano, Melissa J; Anand, Arvind et al. (2018) Sequence Variation of Rare Outer Membrane Protein ?-Barrel Domains in Clinical Strains Provides Insights into the Evolution of Treponema pallidum subsp. pallidum, the Syphilis Spirochete. MBio 9:
Hawley, Kelly L; Cruz, Adriana R; Benjamin, Sarah J et al. (2017) IFN? Enhances CD64-Potentiated Phagocytosis of Treponema pallidum Opsonized with Human Syphilitic Serum by Human Macrophages. Front Immunol 8:1227
Peeling, Rosanna W; Mabey, David; Kamb, Mary L et al. (2017) Syphilis. Nat Rev Dis Primers 3:17073
Puthenveetil, Robbins; Kumar, Sanjiv; Caimano, Melissa J et al. (2017) The major outer sheath protein forms distinct conformers and multimeric complexes in the outer membrane and periplasm of Treponema denticola. Sci Rep 7:13260
Groshong, Ashley M; Dey, Abhishek; Bezsonova, Irina et al. (2017) Peptide Uptake Is Essential for Borrelia burgdorferi Viability and Involves Structural and Regulatory Complexity of its Oligopeptide Transporter. MBio 8:
Radolf, Justin D; Deka, Ranjit K; Anand, Arvind et al. (2016) Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen. Nat Rev Microbiol 14:744-759
Kenedy, Melisha R; Scott 2nd, Edgar J; Shrestha, Binu et al. (2016) Consensus computational network analysis for identifying candidate outer membrane proteins from Borrelia spirochetes. BMC Microbiol 16:141
Seña, Arlene C; Zhang, Xiao-Hui; Li, Trudy et al. (2015) A systematic review of syphilis serological treatment outcomes in HIV-infected and HIV-uninfected persons: rethinking the significance of serological non-responsiveness and the serofast state after therapy. BMC Infect Dis 15:479
Luthra, Amit; Anand, Arvind; Hawley, Kelly L et al. (2015) A Homology Model Reveals Novel Structural Features and an Immunodominant Surface Loop/Opsonic Target in the Treponema pallidum BamA Ortholog TP_0326. J Bacteriol 197:1906-20

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