Molecular T. vaginalis-host interactions in relevance to inflammatory sequelae

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DESCRIPTION (provided by applicant): Trichomoniasis is the most common non-viral sexually transmitted infection (STI) affecting annually over 180 million people worldwide and 8-10 million Americans. It predisposes women to pre-term delivery, low birth weight, cervical cancer, severe inflammation, and increased risk of HIV-1 infection. In about half of the women the infection is asymptomatic and is often recurrent with no lasting immunity suggesting the importance of the innate immune defenses. The isolation and purification of the predominant cell surface glycoconjugate of the parasite, the T. vaginalis (TV) lipophosphoglycan (LPG), has allowed us to study novel molecular interactions between the parasite and the complex vaginal environment. LPG is a glycosylphosphatidyl inositol-like anchored molecule, which unlike other GPI-like parasitic molecules, contains no mannose and has poly-N-acetyllactosamine repeats. We were the first to show that LPG plays a key role in the parasite adhesion and signaling to normal human vaginal epithelial cells. Our latest novel findings suggest that LPG binds galectins expressed by vaginal epithelial cells and may synergize with selected vaginal microflora components specific for bacterial vaginosis (BV), which is a condition known to increase susceptibility to HIV infection. We have identified the structural domain of LPG, the ceramide phosphatidyl-inositol-glycan core (CPI-GC) with m/z 8695.5, as a potential galectin ligand responsible for proinflammatory activation of vaginal and cervical epithelial cells. We hypothesize that T. vaginalis LPG, especially its PI-GC, modulate the host immunoinflammatory environment via binding galectins with opposing functions in the genital mucosa and host immune system and that these events may be facilitated by BV-associated microflora. To test this hypothesis we propose to use a physiologically relevant in vitro model system and correlate our experimental findings with immune responses in a prospectively collected cohort of women with and without BV followed before and after infection with TV and HIV-1. Our specific aims are to: 1) define the roles of galectins as vaginal innate immunity modulators and host receptors for T. vaginalis LPG and identify related signaling pathways operating in the cervicovaginal epithelial cells in the context of normal and BV-associated microflora; 2) elucidate further the biochemical structure of LPG and the CPI-GC subdomains responsible for galectin binding and signaling; and 3) identify and validate molecular patterns of altered vaginal immunity in concurrent trichomoniasis and bacterial vaginosis that may enhance HIV infection risk. The proposed research will expand the understanding of the immune evasion by T. vaginalis. It will elucidate mechanisms underlying increased HIV-1 risk in relations to trichomoniasis and BV, validate diagnostic and prognostic biomarkers of vaginal immune dysregulation and pave the way to novel prevention and treatment strategies. PUBLIC HEALTH RELEVANCE: Trichomonas vaginalis is one of the most common non-viral sexually transmitted infections (trichomoniasis) in the world, which predisposes women to HIV-1 infection, preterm delivery and cancer; over 180 million people world-wide, including 8-10 million Americans become infected annually. With antibiotic resistance to the parasite on the rise, the development of novel prevention strategies based on the advances of molecular medicine is critical. The objective of this study entitled "Molecular T. vaginalis-host interactions in relevance to inflammatory sequelae" is to unveil molecular mechanisms of parasite-host interactions associated with inflammatory symptoms and susceptibility to infection.