Genital infection by obligate intracellular bacterium, Chlamydia trachomatis, is a common sexually transmitted disease in the United States and the complications in women can result in infertility. The need for a vaccine to control the morbidity and public health concerns from genital chlamydial disease has focused research on identifying antigenic candidates for a vaccine, elucidating the cellular and molecular basis for protective immunity, and characterizing local or external factors that regulate genital mucosal immune responses against Chlamydia. In this respect, clinical observation in women have shown that the presence of sex hormones, associated with estrous cycle or through administration of contraceptives or hormonal therapy, could influence the rate and severity of genital chlamydial infection. This observation has been supported by studies in experimental animal models of genital chlamydial disease in mice, rats and guinea pigs. However, the hither-to limited, reliable, gene-based experimental biologic systems precluded the detailed understanding of the precise cellular and molecular basis for hormonal potentiation of genital chlamydial infection. By combining a murine model of chlamydial genital infection with genetically engineered chemokine receptor knockout mice, and specifically designed in vitro culture systems, this grant proposal was designed to investigate the microbiological, immunologic, cellular, molecular and biochemical basis for female sex hormonal control of genital chlamydial disease. The hypothesis to be tested is that female sex hormones (estrogen and/or progesterone) alter the profile of chemokine and chemokine receptor expression during genital chlamydial infection by enhancing epithelia colonization which fosters spreading or ascending infection to the fallopian tubes, delayed immune initiation and clearance of infection. These studies will contribute to a better understanding of the cellular and molecular mechanisms of chamydial immunity, strategies for optimizing the effectiveness of genital mucosal immunity, which may be useful when designing a rational vaccine against Chlamydia.
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