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

描述(由申请人提供)：本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)生物标记物发现和验证(03)，特定主题03-AI-101(可能导致开发具有广谱活性的抗菌剂的新宿主病原体靶标的鉴定、表征和评估)。这项研究涉及到我们对女性生殖道粘膜免疫防御的认识上的重大差距，以及提高诊断、治疗和预防阴道毛滴虫感染的必要性。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800万至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。电视在育龄妇女和低资源社区的普及率最高。这种感染通常是反复发生的，并与早产、低出生体重、艾滋病毒-1感染和可归因于HPV的宫颈癌有关。据估计，治疗滴虫病引起的艾滋病毒感染的终身成本为1.67亿美元。几乎一半感染电视的女性没有症状，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风险因素。对治疗的抵抗率正在上升到惊人的高水平(在我们最近对纽约一个县的调查中，这一比例为25%)。据报道，美国各地都出现了电视抗药性病例。症状差异、缺乏持久免疫力、高复发率和耐药的机制尚不清楚。一些研究已经证明了TV病毒(TVV)在该寄生虫的临床分离株中的存在，但对其遗传学、毒力以及与滴虫病的炎症反应和并发症的相关性知之甚少。初步的体外结果表明，在人阴道上皮细胞中，含有一种或多种TVV的TV株与未携带TVV的株相比，可以诱导更高的炎症反应。有一种假说认为，TVV可以改变阴道黏膜免疫反应，因此是预测/诊断标记物和治疗的一个有吸引力的靶点。这一假设将通过以下具体目标来解决：1)确定TVV-寄生虫-宿主相互作用对阴道粘膜免疫的影响机制；2)建立来自临床TV分离株的TVV的分子遗传学特征；以及3)确定TVV在女性中的患病率和临床意义。这项研究将确定与电视毒力相关的TVV分子特征、免疫逃避机制和药物敏感性。该方法包括一个生理体外模型系统，新的分子生物学技术和工具，以及对在纽约州锡拉丘兹的奥农达加县卫生局性病诊所寻求治疗的妇女进行的调查。这项拟议的研究将扩大对阴道粘膜免疫的基本知识，识别感染风险的新生物标记物，并为根除滴虫病及其对妇女健康的有害影响提出新的治疗和疫苗目标。 公共卫生相关性：阴道毛滴虫(TV)是美国最常见的非病毒性性传播病原体。这种感染是反复发生的，给妇女和儿童带来了沉重的医疗、社会和经济负担。它与炎症、早产和低出生体重、艾滋病毒风险增加和癌症有关。一些TV分离株含有病毒，这可能是医疗并发症严重程度的基础，但迄今尚未确定其特征。本研究的目的是确定TV病毒在逃避阴道黏膜免疫和抵抗治疗中的作用。这项研究将通过解决女性生殖器粘膜基本知识方面的差距，确定新的增加风险的生物标记物以及预防滴虫引起的疾病的治疗目标和战略，促进妇女的健康。

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.