Sexually transmitted diseases (STDs) cause extensive morbidity and are epidemic in many developing countries and in certain segments of the US population. Little is known about immune defense mechanisms of the male urogenital tract that normally limit STD infections or that can be induced to protect against transmission of STD pathogens. Such information would facilitate the development of vaccines and other strategies to prevent STDs. This Program Project application addresses several aspects of this important research area. Three research projects and two service cores (Administrative and Clinical) are proposed. Project 1 (Dr. Anderson, PI) will investigate humoral and cellular acquired immune responses in the male genital tract and their regulation. A special focus of this project will be the molecular definition and functional studies of immunoregulatory molecules and changes in their expression during infection. It is hypothesized that the male urogenital tract is an inductive site for local humoral immunity, but that cellular immune responses are tightly regulated. Project 2 (Dr. Quayle, PI) addresses the role of epithelial defensins (HD-5, HBD-1 and HBD- 2) in early host-pathogen interactions in the male urogenital tract. This project will characterize expression patterns and secreted forms of defensins in normal men and men with STDs, their activity against STD pathogens, and the role of defensins in leukocyte recruitment to the mucosa. Project 3 (Dr. Toribara, PI) will investigate mucin expression at various sites in the male genital tract, and address the hypothesis that mucins play an important role in mucosal immune defense. Investigators workings on Projects 1 (acquired immunity) and 2 (defensins) will collaborate with investigators working on Project 3 (mucins) to define functional interactions between classic immunological mediators (cytokines, immunoglobulins, lymphocytes, defensins) and mucins present in the male genital tract. The Administrative Core will provide infrastructure support for the program. The Clinical Core, codirected by Drs. J. Pudney and P. Rice (PI of the Boston STD-CRC), will provide five services: 1) a male genital tract tissue bank for studies on cellular distribution and expression of defense molecules in different regions of the male genital tract; 2) immortalized epithelial cell lines from prostate, urethra and seminal vesicles and STD organisms for in vitro studies of effects of infection on gene regulation of defense and immunoregulatory molecules; 3) urethral and prostatic secretions from men with specific STDs and controls for studies on regulation of defense mechanisms by natural infections in vivo; 4) a PCR service for screening tissues and clinical samples for specific STD pathogens; and 5) database and statistical support.
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