Syphilis, a classical sexually transmitted disease (STD), remains a significant public health problem in the United States and globally. Cyclic and regional epidemiologic trends, coupled with the fact that syphilitic genital ulcers are cofactors for the transmission of HIV, underscore the importance of continued studies to elucidate the complex pathogenesis epidemiology, and immunology of syphilis. Though one of the oldest recognized STDs, syphilis remains among the most poorly understood, largely due to the fact that Treponema pallidum cannot be cultivated in vitro. Regarding contemporary syphilis research, it is believed that the identification of T. pallidum outer membrane proteins (OMPs) potentially represents the """"""""Holy Grail"""""""" of syphilis immunology; that is, once identified, they may be formulated into vaccines that could elicit bactericidal antibodies. However, the identification of T. pallidum OMPs has been highly problematic; to date, not a single OMP of T. pallidum has been definitively identified. Nonetheless, the indentification of OMPs of T. pallidum remains a laudable goal of syphilis research that must continue. To this end, Specific Aim 1 of this proposal will implement a new, highly sensitive, surface-labeling technique to identify candidate OMPs in T. pallidum. Three candidates already have been identified in preliminary studies. Putative OMPs identified in this manner, along with other candidates, will be subjected to more rigorous membrane topology studies in T. pallidum (Specific Aim 2). Finally, past attempts to demonstrate the efficacy of selected recombinant treponemal antigens in classical vaccine studies with rabbits have not been fruitful. To move syphilis vaccine development to the next level of more modern vaccinology, we will apply contemporary genetic immunization strategies to rabbits (Specific Aim 3) using OMP candidates emanating from Specific Aims 1 and 2. We already have evidence that genetically engineered treponemal proteins can be expressed in rabbit cells. The combined studies will substantially advance our knowledge of the relationships between T. pallidum membrane architecture, syphilis pathogenesis, and protective immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI016692-26
Application #
7032999
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Hiltke, Thomas J
Project Start
1980-05-01
Project End
2010-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
26
Fiscal Year
2006
Total Cost
$492,260
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Scheuermann, Thomas H; Brautigam, Chad A (2015) High-precision, automated integration of multiple isothermal titration calorimetric thermograms: new features of NITPIC. Methods 76:87-98
Sheffield, Jeanne S; Wendel Jr, George D; McIntire, Donald D et al. (2009) The effect of progesterone levels and pregnancy on HIV-1 coreceptor expression. Reprod Sci 16:20-31
Tomson, Farol L; Conley, Patrick G; Norgard, Michael V et al. (2007) Assessment of cell-surface exposure and vaccinogenic potentials of Treponema pallidum candidate outer membrane proteins. Microbes Infect 9:1267-75
Sheffield, Jeanne S; Wendel Jr, George D; McIntire, Donald D et al. (2007) Effect of genital ulcer disease on HIV-1 coreceptor expression in the female genital tract. J Infect Dis 196:1509-16
Deka, Ranjit K; Goldberg, Martin S; Hagman, Kayla E et al. (2004) The Tp38 (TpMglB-2) lipoprotein binds glucose in a manner consistent with receptor function in Treponema pallidum. J Bacteriol 186:2303-8
Lee, Yong-Hwan; Dorwart, Michael R; Hazlett, Karsten R O et al. (2002) The crystal structure of Zn(II)-free Treponema pallidum TroA, a periplasmic metal-binding protein, reveals a closed conformation. J Bacteriol 184:2300-4
Deka, Ranjit K; Machius, Mischa; Norgard, Michael V et al. (2002) Crystal structure of the 47-kDa lipoprotein of Treponema pallidum reveals a novel penicillin-binding protein. J Biol Chem 277:41857-64
Bouis, D A; Popova, T G; Takashima, A et al. (2001) Dendritic cells phagocytose and are activated by Treponema pallidum. Infect Immun 69:518-28
Sellati, T J; Wilkinson, D A; Sheffield, J S et al. (2000) Virulent Treponema pallidum, lipoprotein, and synthetic lipopeptides induce CCR5 on human monocytes and enhance their susceptibility to infection by human immunodeficiency virus type 1. J Infect Dis 181:283-93
Deka, R K; Lee, Y H; Hagman, K E et al. (1999) Physicochemical evidence that Treponema pallidum TroA is a zinc-containing metalloprotein that lacks porin-like structure. J Bacteriol 181:4420-3

Showing the most recent 10 out of 53 publications