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

阴道毛滴虫病毒作为粘膜免疫调节剂对女性健康有影响

• 批准号: 8494163
• 负责人: RAINA N. FICHOROVA
• 金额: $ 87.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494163
• 关键词: Address; Adverse effects; Affect; African American; Age; American; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antiviral Agents; Attenuated; Basic Science; Biochemical; Biological Assay; Biological Markers; Biological Models; Blocking Antibodies; Cell Line; Cervical; Characteristics; Child; Child health care; Chlamydia; Clinical; Communities; Data; Diagnosis; Diagnostic; Disease; Dose; Double Stranded RNA Virus; Double-Stranded RNA; Drug resistance; Economic Burden; Enrollment; Epidemiology; Epithelial; Epithelial Cells; Female; Gene Silencing; Genes; Genetic; Genetic Polymorphism; Genital system; Genotype; Gonorrhea; HIV; HIV Infections; Host resistance; Human; Human Papillomavirus; IL8 gene; Immune; Immune response; Immunity; In Vitro; Incidence; Individual; Infection; Infection prevention; Inflammation; Inflammatory; Inflammatory Response; Interferon Type I; Knowledge; Laboratories; Link; Low Birth Weight Infant; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediator of activation protein; Medical; Medical Economics; Membrane; Messenger RNA; Methods; Metronidazole; Minority; Modeling; Molecular; Molecular Biology Techniques; Mucosal Immunity; Natural Immunity; Nature; Parasites; Pathology; Pathway interactions; Pelvic Inflammatory Disease; Pharmaceutical Preparations; Physiological; Plasmids; Population; Predisposition; Pregnant Women; Prevalence; Prevention strategy; Prevention therapy; Production; Prognostic Marker; Proteins; Public Health; Publishing; RNA Interference; Reaction; Recurrence; Regulation; Reporter; Research; Resistance; Resources; Ribavirin; Risk; Risk Factors; Role; Severities; Sexually Transmitted Diseases; Signal Transduction; Solid; Structure-Activity Relationship; Surveys; Symptoms; TLR3 gene; Techniques; Term Birth; Testing; Therapeutic; Time; Transfection; Translational Research; Trichomonas Infections; Trichomonas vaginalis; Vaccines; Vagina; Vaginitis; Virion; Virulence; Virulence Factors; Virus; Virus Diseases; Weight Gain; Woman; Women' s Health; high risk; immune function; improved; in vitro Model; interdisciplinary approach; life time cost; lipophosphonoglycan; medical complication; new therapeutic target; novel; novel diagnostics; pathogen; prognostic; receptor; reproductive; response; sensor; social; tool; transmission process; viral RNA

DESCRIPTION (provided by applicant): This 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 and worldwide. 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 with an enormous racial disparity (1.5 to 10 times more prevalent in African-American women from urban communities). Among TV-attributable risks and pathologies disproportionately affecting minority populations are pre-term birth, low birth weight, cervical cancer, and higher risk of HIV. The estimated lifetime cost of treating trichomoniasis-attributable HIV infections is $167 million. Resistance to the current drug of choice, metronidazole, is rising to alarmingly high rates, and pregnant women treated with metronidazole are at even higher risk of pre-term birth. 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 mechanisms of symptom disparity, lack of lasting immunity, high recurrence rate, and resistance to treatment are unknown. Several studies including ours have documented the presence of TV-specific dsRNA viruses (TVVs) in clinical isolates of the parasite, but little is known about their genetics, virulence, relevance to the inflammatory reaction, drug resistance, and medical complications of trichomoniasis. Our recently published data show the simultaneous presence of as many as 4 distinct species of TVVs in clinical TV isolates from women with vaginitis. Furthermore, we have demonstrated that in genital epithelial cells, TV strains harboring one or more TVVs induce a heightened, virus- dependent inflammatory response. We propose a novel hypothesis that implicates TVVs as modifiers of TV virulence and as factors underlying symptom disparity of TV infections and current therapy's side effects, thus emerging as key targets for prognostic/diagnostic biomarkers and new therapies. This hypothesis will be addressed by the following Specific Aims: (1) discover novel molecular determinants of TVV-TV-human interactions with impact on vaginal epithelial immune function (2) define genetic, biochemical, and biophysical characteristics of TVVs with impact on TV virulence and vaginal immune function that could be used for diagnostic or therapeutic approaches; (3) collect and examine clinically defined primary TV isolates to link distinct TVV genotypes and molecular characteristics to drug resistance and symptomatic trichomoniasis in a US population most vulnerable to TV-attributable disease. Our interdisciplinary approach includes a physiological in-vitro model system, novel molecular biology techniques and isogenic tools, as well as a survey of women seeking treatment for trichomoniasis. The proposed translational research will generate new basic knowledge of vaginal immunity and infection risk factors with high impact on women's and children's health.

描述（由申请人提供）：这项研究涉及我们对女性生殖道粘膜免疫防御能力的关键差距，以及改善Trichomonas阴道（TV）对诊断，治愈和预防感染的需求，这是美国和全球最常见的非病毒性传播病原体。感染（trichomonisis）每年影响8-1亿美国人，尤其是对妇女和儿童的严重医疗，经济和社会影响。在生殖时代和低资源社区中，电视的流行最高，具有巨大的种族差异（来自城市社区的非裔美国妇女中的普遍存在1.5至10倍）。在电视征收的风险和病理中，影响少数群体人口的比例过高，是预期出生，低出生体重，宫颈癌和艾滋病毒风险较高。治疗毛诺病 - 可杀入的艾滋病毒感染的寿命估计成本为1.67亿美元。对当前选择的药物甲硝唑的抵抗力正在提高到令人震惊的高率，而接受甲硝唑治疗的孕妇的孕妇的孕妇的耐药性更高。几乎一半的电视感染女性无症状，而其他女性则出现严重的生殖器炎症，这是艾滋病毒获取的额外危险因素。症状差异的机制，缺乏持久的免疫力，高复发率和对治疗的抵抗力尚不清楚。包括我们在内的几项研究记录了寄生虫临床分离株中电视特异性DSRNA病毒（TVV）的存在，但对它们的遗传学，毒力，与炎症反应，耐药性，耐药性和trichomoniasis医疗并发症相关的知之甚少。我们最近发表的数据显示，来自阴道炎女性的临床电视分离株中，同时存在多达4种不同的TVV。此外，我们已经证明，在生殖器上皮细胞中，带有一个或多个TVV的电视菌株会诱导增强的病毒依赖性炎症反应。我们提出了一个新的假设，该假设将TVV作为电视毒力的修饰符以及电视感染的症状差异和当前疗法的副作用，从而成为预后/诊断生物标志物和新疗法的关键目标。以下特定目的将解决该假设：（1）发现TVV-TV-Human相互作用的新型分子决定因素，对阴道上皮免疫功能的影响（2）定义了对TVVV的遗传，生化和生物物理特征，对TVVV的电视和阴道免疫功能的影响，可用于诊断或具有诊断性的方法。 （3）收集和检查临床定义的主要电视分离株，以将不同的TVV基因型和分子特征与耐药性和有症状性三甲虫病的分子特征联系起来，这是美国最容易受到电视 - 可侵蚀性疾病的影响。我们的跨学科方法包括一种生理学内模型系统，新型分子生物学技术和等源性工具，以及对寻求治疗trichomoniasis治疗的妇女的调查。拟议的翻译研究将对阴道免疫和感染风险因素产生新的基本知识，并对妇女和儿童的健康产生很大影响。