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

描述（由申请人提供）：该申请涉及广泛的挑战领域：1)临床研究（04），特定主题04- ai -101*（开发新方法并解决粘膜免疫学中的关键问题），以及2)生物标志物发现和验证（03），特定主题03- ai -101（鉴定，表征和评估可能导致开发具有广谱活性的抗菌剂的新型宿主病原体靶点）。该研究解决了我们对女性生殖道粘膜免疫防御的理解的关键空白，以及改善阴道毛滴虫（TV）感染的诊断、治疗和预防的需要，阴道毛滴虫是美国最常见的非病毒性性传播病原体。这种感染（滴虫病）每年影响800 - 1000万美国人，造成严重的医疗、经济和社会后果，特别是对妇女和儿童。在育龄妇女和资源贫乏的社区，电视的流行率最高。这种感染通常是复发性的，与早产、低出生体重、HIV-1感染和由HPV引起的宫颈癌有关。治疗由滴虫病引起的艾滋病毒感染的估计终生费用为1.67亿美元。几乎一半受电视感染的妇女没有症状，而其他人则出现严重的生殖器炎症，这是感染艾滋病毒的另一个危险因素。对治疗的抵抗率上升到惊人的高（在我们最近对纽约一个县的调查中，高达25%）。美国各地都报道了耐药的电视病例。其症状差异、缺乏持久免疫、复发率高、耐药等机制尚不清楚。一些研究已经证实在临床分离的滴虫中存在TV病毒（TVVs），但对其遗传、毒力以及与滴虫病炎症反应和并发症的相关性知之甚少。初步的体外实验结果表明，在人阴道上皮细胞中，与不含TVV的菌株相比，含有一种或多种TVV的TV菌株诱导的炎症反应更高。一种假设是tvv改变了阴道粘膜免疫反应，因此代表了预后/诊断标记和治疗的一个有吸引力的目标。这一假设将通过以下具体目标来解决：1)确定电视-寄生虫-宿主相互作用对阴道黏膜免疫影响的机制；2)建立临床电视分离株衍生电视病毒的分子遗传学特征；3)确定女性TVV患病率及临床意义。本研究将明确电视病毒的分子特征，包括电视病毒的毒力、免疫逃避机制和药物敏感性。该方法包括生理体外模型系统，新的分子生物学技术和工具，以及在纽约州锡拉丘兹奥农达加县卫生部门性病诊所寻求治疗的妇女的调查。该研究将扩展阴道粘膜免疫的基础知识，确定感染风险的新生物标志物，并为根除滴虫病及其对妇女健康的有害影响提供新的治疗和疫苗靶点。

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.