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）：本研究涉及我们对女性生殖道粘膜免疫防御的理解的关键空白，以及提高阴道毛滴虫（TV）感染的诊断、治疗和预防的需要，阴道毛滴虫是美国和世界范围内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。电视在育龄妇女和资源匮乏、种族差异巨大的社区的普及程度最高（在城市社区的非裔美国妇女中普及程度是前者的1.5至10倍）。在影响少数民族人口的电视归因风险和病理中，早产、低出生体重、子宫颈癌和艾滋病毒风险较高。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。对目前的首选药物甲硝唑的耐药性上升到令人震惊的高水平，而接受甲硝唑治疗的孕妇早产的风险甚至更高。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。其症状差异、缺乏持久免疫、复发率高、耐药等机制尚不清楚。包括我们在内的几项研究已经证实，在临床分离的滴虫中存在tv特异性dsRNA病毒（TVVs），但对它们的遗传、毒力、与炎症反应的相关性、耐药性和滴虫病的医学并发症知之甚少。我们最近发表的数据显示，在患有阴道炎的女性的临床电视分离株中，同时存在多达4种不同的电视分离株。此外，我们已经证明，在生殖器上皮细胞中，含有一个或多个tvv的TV菌株诱导了高度的病毒依赖性炎症反应。我们提出了一个新的假设，认为电视病毒是电视毒力的修饰因子，是电视感染症状差异和当前治疗副作用的潜在因素，因此成为预后/诊断生物标志物和新疗法的关键靶点。这一假设将通过以下具体目标来解决：(1)发现影响阴道上皮免疫功能的电视-电视-人相互作用的新分子决定因素(2)确定影响电视毒力和阴道免疫功能的电视病毒的遗传、生化和生物物理特征，这些特征可用于诊断或治疗方法；(3)收集并检查临床确定的原TV分离株，以在美国最易患TV归因疾病的人群中，将不同的TV基因型和分子特征与耐药性和症状性滴虫病联系起来。我们的跨学科方法包括生理体外模型系统，新型分子生物学技术和等基因工具，以及对寻求滴虫病治疗的妇女的调查。拟议的转化研究将产生对妇女和儿童健康有重大影响的阴道免疫和感染危险因素的新基本知识。