Determining the importance of in vivo estrogen receptors and in vitro hormone modulation of Wnt/?- catenin signaling on Chlamydia infections. Project Summary Naturally fluctuating levels of the hormones, estrogen and progesterone, alter the occurrence and/or severity of sexually transmitted infections (STIs). An estimated 150 million women worldwide use hormonal contraceptives containing combinations of synthetic estrogen and/or progesterone. C. trachomatis annually causes 1,400,000 infections in the US and remains the most frequent bacterial STI worldwide. The non-invasive, sexually transmitted C. trachomatis serovars D-K are obligate intracellular pathogens that replicate primarily within female genital tract (FGT) luminal and glandular epithelial cells. If untreated, these organisms can ascend the FGT, evoking pelvic inflammatory disease, infertility and ectopic pregnancy in infected women. Clinical trials, animal models and in vitro studies all suggest that estrogen enhances chlamydial infection by multiple mechanisms. Steroid hormones have both direct and indirect effects on endometrial epithelial cells and also induce endometrial stromal cells to release effector molecules that regulate growth and maturation of uterine epithelial cells. Previously, we investigated the effects of hormones on chlamydial infection in an endometrial epithelial cell (Ishikawa, IK)/stromal cell (SHT-290) co-culture system, which provides a unique opportunity to dissect complex hormone/stromal cell/epithelial cell interactions in a simplified in vitro setting. Data from these studies indicate that: i) membrane-associated estrogen receptors help mediate C. trachomatis serovar E entry into host genital epithelial cells; ii) estrogen receptor signaling facilitates intracellular development of C. trachomatis; iii) estrogen-stimulated endometrial stromal cells secrete effectors that indirectly aid intracellular chlamydial development in genital epithelial cells, and; iv) progesterone antagonizes the effects of estrogen on chlamydial development. Published reports indicate that the Wnt/?-catenin signaling pathway is important for C. trachomatis development. Interestingly, estrogen activates Wnt signaling whereas progesterone inhibits Wnt signaling in the FGT. This proposal will test two independent, but related, hypotheses. First, in hormone- exposed co-cultures, estrogen-activation of Wnt/?-catenin signaling contributes to estrogen-mediated enhancement of C. trachomatis infections whereas progesterone negatively effects C. trachomatis development by inhibiting Wnt. Second, the establishment and/or progression of chlamydial infection in vivo will be inhibited in the absence of estrogen receptors. Data from these experiments will: i) increase understanding of how hormones modulate chlamydial infection, transmission and reproductive pathology; and ii) determine the feasibility of analyzing the effects of estrogen receptor-independent signaling on chlamydial infection in vivo.
The bacterium Chlamydia trachomatis causes more than 1.4 million infections annually in the US with the majority of cases occurring in women of child bearing age (14-29 year old). There is evidence that the sex hormones, estrogen and progesterone, can modulate the severity of chlamydial infections. This study will provide information on mechanisms by which sex hormones influence C. trachomatis disease progression.