This Program Project application focuses on the paralogous 12-mernber tpr family of Treponema pallidum, the causatiye;agent of syphilis. Evidence suggests; that these: genes; and their encoded proteins, are important antigens and virulence factors. We propose to examine TprK, one member of the Tpr family, as:the first angenic variation system to bedescribed in Treponema pallidum. TprK is a major target of both cellular and humoral immunity and immunization rabbits with recombinant TprK results in significant attenuation of lesion development following intradermal challenge with viable Treponema pallidum. TprK is heterogeneous among and within strains* with sequence variation limited to 7 discrete variable (V) that are targets of the antibody response. A molecular mechanism has been proposed for the sequence variation, with mutations arising in the single tprK expression site by gene conversion of donor sites located near tprD on the chromosome. Using a novel method for derivation of clonal isolates of T. pallidum, we have demonstrated that the tprK V region sequences change during infection, and that variation accumulates under immune pressure. These findings strongly suggest the role of tprK variation in immune evasion and persistence of infection. In this renewal application, we propose the following Specific Aims: 1). Compare the pattern and rate of tprK sequence change among three strains of T. pallidum during the course of infection and during serial passage; 2). Determine whether immunosuppression prevents accumulation of variant sequences during infection; 3). Determine whether V region-specific immune pressure selects for organisms with variant tprK sequences; 4). Determine the contribution of TprK V region sequence diversity in susceptibility to heterologous infection or immune escape. These studies, in concert with the aims of Projects 1-3, will help to define mechanisms of pathogenesis and persistence of this important infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1-MH-M (M1))
Program Officer
Hiltke, Thomas J
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Molini, Barbara J; Tantalo, Lauren C; Sahi, Sharon K et al. (2016) Macrolide Resistance in Treponema pallidum Correlates With 23S rDNA Mutations in Recently Isolated Clinical Strains. Sex Transm Dis 43:579-83
Giacani, Lorenzo; Brandt, Stephanie L; Ke, Wujian et al. (2015) Transcription of TP0126, Treponema pallidum putative OmpW homolog, is regulated by the length of a homopolymeric guanosine repeat. Infect Immun 83:2275-89
Reid, Tara B; Molini, Barbara J; Fernandez, Mark C et al. (2014) Antigenic variation of TprK facilitates development of secondary syphilis. Infect Immun 82:4959-67
Giacani, Lorenzo; Lukehart, Sheila A (2014) The endemic treponematoses. Clin Microbiol Rev 27:89-115
Cameron, Caroline E; Lukehart, Sheila A (2014) Current status of syphilis vaccine development: need, challenges, prospects. Vaccine 32:1602-9
Lukehart, Sheila A; Giacani, Lorenzo (2014) When is syphilis not syphilis? Or is it? Sex Transm Dis 41:554-5
Centurion-Lara, Arturo; Giacani, Lorenzo; Godornes, Charmie et al. (2013) Fine analysis of genetic diversity of the tpr gene family among treponemal species, subspecies and strains. PLoS Negl Trop Dis 7:e2222
Grimes, Matthew; Sahi, Sharon K; Godornes, B Charmie et al. (2012) Two mutations associated with macrolide resistance in Treponema pallidum: increasing prevalence and correlation with molecular strain type in Seattle, Washington. Sex Transm Dis 39:954-8
Giacani, Lorenzo; Chattopadhyay, Sujay; Centurion-Lara, Arturo et al. (2012) Footprint of positive selection in Treponema pallidum subsp. pallidum genome sequences suggests adaptive microevolution of the syphilis pathogen. PLoS Negl Trop Dis 6:e1698
Giacani, Lorenzo; Brandt, Stephanie L; Puray-Chavez, Maritza et al. (2012) Comparative investigation of the genomic regions involved in antigenic variation of the TprK antigen among treponemal species, subspecies, and strains. J Bacteriol 194:4208-25

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