T. vaginalis is one of the most common non-viral sexually transmitted infections (trichomoniasis) in the world. Trichomoniasis has been linked to increased incidence of pre-term delivery, low birth weight, cervical cancer, HIV-1 transmission and vaginitis possibly via induction of inflammatory cytokines and poorly understood immunoregulatory interactions in the reproductive tract mucosa. It is unclear why almost half of the women diagnosed with trichomoniasis are asymptomatic while the other half develops symptoms of severe inflammatory reaction. We have isolated, purified and partially characterized lipophosphoglycan (LPG), the main cell surface glycoconjugate of the parasite, which has enabled us to study host-parasite interactions at the molecular level. The results from our initial investigations demonstrate that T. vaginalis (TV) LPG mediates the adhesion of parasites to human vaginal epithelial cells and stimulates the induction of chemokines in human monocytes and squamous epithelial cell types representing the lower female genital tract mucosa. Our results also demonstrate that chemokines are induced in vaginal and cervical epithelial cells independently of cytokines released by cell damage. We hypothesize that TV LPG triggers the mucosal inflammatory reaction by signaling via receptors on the reproductive tract epithelial cells. The proposed mechanism involves NF-KB activation, upregulation of cytokines and chemokines and modulation of epithelial immunoregulatory pathways. We propose to test our hypothesis by the following specific aims: (1) characterize paracrine responses to TV LPG, including production of cytokines/chemokines and pathways operating in the human vaginal, ectocervical and endocervical epithelial cells, (2) determine whether these effects are mediated through Toll receptors, and (3) what domain(s) of the LPG molecule are required for initiating and sustaining or suppressing these inflammatory responses. The proposed research will expand the understanding of the immune evasion mechanisms exploited by T. vaginalis and may provide potential diagnostic and prognostic disease markers for clinical validation. Host response pathways identified by the proposed research may be translated into future clinical studies on mechanisms underlying reproductive failure, cancer and susceptibility to HIV-1 infection associated with trichomoniasis and may assist the development of new vaccine and drug targets to prevent and cure T. vaginalis infections and complications. ? ? ?
