Syphilis is a chronic bacterial infection which, after five centuries, continues to plague individuals worldwide. Although effective therapy has been available for fifty years, the United States is currently in the midst of a syphilis epidemic, with a 50% increase in incidence in the past two years. In addition to the serious late sequelae of syphilis, numerous studies suggest that syphilis and other genital ulcer diseases may be risk factors for acquisition and transmission of human immunodeficiency virus (HIV) infection. The immune response to syphilis infection has been under investigation for a number of years, however a clear understanding of the specific mechanisms of resistance has not yet been achieved. Antibody, which is produced in high titer during infection, can neutralize, immobilize, and opsonize T. pallidum, yet its importance in lesion resolution and resistance is unknown. Based upon histological and laboratory studies, it is generally accepted that the cellular arm of the immune system is central to the clearance of syphilitic lesions and the development of resistance. Our working hypothesis of syphilis immunity centers around the production of lymphokines (macrophage activating factors [MAF], including gamma-interferon) by specifically sensitized lymphocytes with the resultant activation of effector macrophages which are primarily responsible for bacterial clearance. Although a number of Treponema pallidum antigens have been identified and characterized in terms of antibody reactivity, little is known about the antigens which induce cellular immune responses. In order to focus future vaccine studies on molecules which are known to stimulate the specific cellular functions believed to be central to syphilis immunity, this renewal application proposes the examination of individual antigens of T. pallidum in terms of their interaction with macrophages and lymphocytes in the induction and development of these cellular responses. Specifically, we propose 1) the identification of antigenic molecules and peptides of T. pallidum which stimulate production of macrophage activating factors (MAF) by sensitized lymphocytes in vitro and induce delayed hypersensitivity in vivo 2) the examination of the nature of antigen processing and kinetics of presentation of individual antigens by macrophages in order to characterize molecules and determinants which readily induce appropriate T lymphocyte responses; 3) the development of T cell clones with specificity for T. pallidum antigens for use in antigen presentation assays and for examination of lymphokine production in response to individual T cell epitopes; 4) the immunization of rabbits with T. pallidum antigens incorporated into liposomes; and 5) the examination of the parameters of phagocytosis of T pallidum and the effector function of macrophages on T. pallidum. We anticipate that these studies will aid in the understanding of the mechanisms of immunity to T. pallidum and will identify specific antigens or epitopes which stimulate protective cellular immune functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018988-09
Application #
3128410
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1984-03-01
Project End
1993-11-30
Budget Start
1992-03-01
Budget End
1993-11-30
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Cameron, C E; Castro, C; Lukehart, S A et al. (1999) Sequence conservation of glycerophosphodiester phosphodiesterase among Treponema pallidum strains. Infect Immun 67:3168-70
Centurion-Lara, A; Castro, C; Barrett, L et al. (1999) Treponema pallidum major sheath protein homologue Tpr K is a target of opsonic antibody and the protective immune response. J Exp Med 189:647-56
Centurion-Lara, A; Castro, C; Castillo, R et al. (1998) The flanking region sequences of the 15-kDa lipoprotein gene differentiate pathogenic treponemes. J Infect Dis 177:1036-40
Cameron, C E; Castro, C; Lukehart, S A et al. (1998) Function and protective capacity of Treponema pallidum subsp. pallidum glycerophosphodiester phosphodiesterase. Infect Immun 66:5763-70
Centurion-Lara, A; Castro, C; Shaffer, J M et al. (1997) Detection of Treponema pallidum by a sensitive reverse transcriptase PCR. J Clin Microbiol 35:1348-52
Stebeck, C E; Shaffer, J M; Arroll, T W et al. (1997) Identification of the Treponema pallidum subsp. pallidum glycerophosphodiester phosphodiesterase homologue. FEMS Microbiol Lett 154:303-10
Centurion-Lara, A; Arroll, T; Castillo, R et al. (1997) Conservation of the 15-kilodalton lipoprotein among Treponema pallidum subspecies and strains and other pathogenic treponemes: genetic and antigenic analyses. Infect Immun 65:1440-4
Marra, C M; Longstreth Jr, W T; Maxwell, C L et al. (1996) Resolution of serum and cerebrospinal fluid abnormalities after treatment of neurosyphilis. Influence of concomitant human immunodeficiency virus infection. Sex Transm Dis 23:184-9
Van Voorhis, W C; Barrett, L K; Koelle, D M et al. (1996) Primary and secondary syphilis lesions contain mRNA for Th1 cytokines. J Infect Dis 173:491-5
Centurion-Lara, A; Castro, C; van Voorhis, W C et al. (1996) Two 16S-23S ribosomal DNA intergenic regions in different Treponema pallidum subspecies contain tRNA genes. FEMS Microbiol Lett 143:235-40

Showing the most recent 10 out of 33 publications