T. vaginalis viruses as mucosal immunity modifiers with impact on women's health

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): This application addresses Broad Challenge Areas: 1) Clinical Research (04), specific topic 04-AI-101* (Develop novel methods and address key questions in mucosal immunology), and 2) Biomarker Discovery and Validation (03), specific topic 03-AI-101 (Identification, characterization and evaluation of novel host pathogen targets that may lead to the development of antimicrobials with broad spectrum activity). The study deals with critical gaps in our understanding of the mucosal immune defenses of the female genital tract and the need to improve diagnosis, cure, and prevention of infection by Trichomonas vaginalis (TV), which is the most common nonviral sexually transmitted pathogen in the US. The infection (trichomoniasis) affects 8-10 million Americans each year with serious medical, economic, and social consequences especially for women and children. The prevalence of TV is highest in women of reproductive age and in low-resource communities. The infection is often recurrent and linked to pre-term delivery, low birth weight, HIV-1 infection, and cervical cancer attributable to HPV. The estimated lifetime cost of treating trichomoniasis-attributable HIV infections is $167 million. Almost half of TV-infected women are asymptomatic while the others develop a severe genital inflammation, which is an additional risk factor for HIV acquisition. The resistance to therapy is rising to alarmingly high rates (>25% in our recent survey of a NY County). Drug-resistant cases of TV have been reported across the US. The mechanisms of symptom disparity, lack of lasting immunity, high recurrence rate, and resistance to treatment are unknown. A few studies have documented the presence of TV viruses (TVVs) in clinical isolates of the parasite, but little is known about their genetics, virulence, and relevance to the inflammatory reaction and complications in trichomoniasis. Preliminary in vitro results show that in human vaginal epithelial cells TV strains harboring one or more strains of TVV induce a heightened inflammatory response in comparison to TVV-free strains. A hypothesis is generated that TVVs modify the vaginal mucosal immune responses and thus represent an attractive target for prognostic/diagnostic markers and therapy. This hypothesis will be addressed by the following specific aims: 1) identify mechanisms of TVV-parasite-host interactions with impact on vaginal mucosal immunity; 2) establish molecular-genetic characteristics of TVVs derived from clinical TV isolates; and 3) determine prevalence and clinical significance of TVV in women. The study will define TVV molecular characteristics related to TV virulence, mechanisms of immune evasion, and drug susceptibility. The approach includes a physiological in vitro model system, novel molecular biology techniques and tools, and a survey of women seeking treatment in the Onondaga County Health Department STD clinic in Syracuse, NY. The proposed research will expand the basic knowledge of vaginal mucosal immunity, identify novel biomarkers of infection risk, and suggest new therapeutic and vaccine targets for eradication of trichomoniasis and its deleterious impact on women's health. PUBLIC HEALTH RELEVANCE: Trichomonas vaginalis (TV) is the most common nonviral sexually transmitted infectious agent in the US. The infection is recurrent and poses heavy medical, social, and economic burdens for women and children. It is linked to inflammation, pre-term delivery and low birth weight, increased risk of HIV, and cancer. Some TV isolates contain virus (es), which may underlie the severity of the medical complications but have not been characterized to date. The purpose of our study is to determine the role of TV viruses in evading the vaginal mucosal immunity and resistance to therapy. The study will promote women's health by addressing gaps in the basic knowledge of the female genital mucosa and identifying novel biomarkers of increased risk as well as therapeutic targets and strategies for prevention of Trichomonas-attributable disease.