Molecular T. vaginalis-host interactions in relevance to inflammatory sequelae

与炎症后遗症相关的分子阴道毛滴虫-宿主相互作用

• 批准号: 7881724
• 负责人: RAINA N. FICHOROVA
• 金额: $ 76.53万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7881724
• 关键词: Adherence; Adhesions; Affect; Affinity; American; Antibiotics; Bacterial Vaginosis; Binding; Biochemical; Biological Markers; Biological Models; Blocking Antibodies; Cell surface; Cells; Ceramides; Cervical; Child; Clinical; Complex; Development; Diagnosis; Diagnostic; Disease Marker; Environment; Epidemiologic Studies; Epithelial Cells; Epithelium; Event; Functional disorder; Galactose Binding Lectin; Galactosides; Genital system; Glycoconjugates; HIV; HIV Infections; HIV-1; Human; Immune; Immune response; Immune system; Immunity; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inositol; Intervention; Laboratories; Lead; Lectin; Life; Ligands; Link; Lipids; Low Birth Weight Infant; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mannose; Mass Spectrum Analysis; Medical Economics; Molecular; Molecular Medicine; Mucous Membrane; N-acetyllactosamine; Natural Immunity; Parasite resistance; Parasites; Pathway interactions; Pattern; Phosphatidylinositols; Play; Polysaccharides; Predisposition; Premature Birth; Prevention; Prevention strategy; Probiotics; Process; RNA Interference; Reaction; Recurrence; Research; Risk; Risk Factors; Role; Sampling; Sexually Transmitted Diseases; Signal Pathway; Signal Transduction; Specimen; Structure; Symptoms; Syndrome; Techniques; Testing; Therapeutic Intervention; Trichomonas Infections; Trichomonas vaginalis; Vagina; Vaginitis; Viral; Woman; base; cohort; endotoxin receptor; gain of function; high risk; immune function; in vitro Model; lipophosphonoglycan; mutant; novel; novel diagnostics; poly-N-acetyllactosamine; prognostic; public health relevance; receptor; research study; response; social; transmission process; treatment strategy; vaginal lactobacilli

DESCRIPTION (provided by applicant): Trichomoniasis is the most common non-viral sexually transmitted infection (STI) affecting annually over 180 million people worldwide and 8-10 million Americans. It predisposes women to pre-term delivery, low birth weight, cervical cancer, severe inflammation, and increased risk of HIV-1 infection. In about half of the women the infection is asymptomatic and is often recurrent with no lasting immunity suggesting the importance of the innate immune defenses. The isolation and purification of the predominant cell surface glycoconjugate of the parasite, the T. vaginalis (TV) lipophosphoglycan (LPG), has allowed us to study novel molecular interactions between the parasite and the complex vaginal environment. LPG is a glycosylphosphatidyl inositol-like anchored molecule, which unlike other GPI-like parasitic molecules, contains no mannose and has poly-N-acetyllactosamine repeats. We were the first to show that LPG plays a key role in the parasite adhesion and signaling to normal human vaginal epithelial cells. Our latest novel findings suggest that LPG binds galectins expressed by vaginal epithelial cells and may synergize with selected vaginal microflora components specific for bacterial vaginosis (BV), which is a condition known to increase susceptibility to HIV infection. We have identified the structural domain of LPG, the ceramide phosphatidyl-inositol-glycan core (CPI-GC) with m/z 8695.5, as a potential galectin ligand responsible for proinflammatory activation of vaginal and cervical epithelial cells. We hypothesize that T. vaginalis LPG, especially its PI-GC, modulate the host immunoinflammatory environment via binding galectins with opposing functions in the genital mucosa and host immune system and that these events may be facilitated by BV-associated microflora. To test this hypothesis we propose to use a physiologically relevant in vitro model system and correlate our experimental findings with immune responses in a prospectively collected cohort of women with and without BV followed before and after infection with TV and HIV-1. Our specific aims are to: 1) define the roles of galectins as vaginal innate immunity modulators and host receptors for T. vaginalis LPG and identify related signaling pathways operating in the cervicovaginal epithelial cells in the context of normal and BV-associated microflora; 2) elucidate further the biochemical structure of LPG and the CPI-GC subdomains responsible for galectin binding and signaling; and 3) identify and validate molecular patterns of altered vaginal immunity in concurrent trichomoniasis and bacterial vaginosis that may enhance HIV infection risk. The proposed research will expand the understanding of the immune evasion by T. vaginalis. It will elucidate mechanisms underlying increased HIV-1 risk in relations to trichomoniasis and BV, validate diagnostic and prognostic biomarkers of vaginal immune dysregulation and pave the way to novel prevention and treatment strategies. PUBLIC HEALTH RELEVANCE: Trichomonas vaginalis is one of the most common non-viral sexually transmitted infections (trichomoniasis) in the world, which predisposes women to HIV-1 infection, preterm delivery and cancer; over 180 million people world-wide, including 8-10 million Americans become infected annually. With antibiotic resistance to the parasite on the rise, the development of novel prevention strategies based on the advances of molecular medicine is critical. The objective of this study entitled "Molecular T. vaginalis-host interactions in relevance to inflammatory sequelae" is to unveil molecular mechanisms of parasite-host interactions associated with inflammatory symptoms and susceptibility to infection.

描述（由申请人提供）：滴虫病是最常见的非病毒性传播感染（STI），每年影响全球超过1.8亿人，而美国人有8-1亿美国人。它使妇女易于期前分娩，低出生体重，宫颈癌，严重的炎症以及HIV-1感染的风险增加。在大约一半的妇女中，感染是无症状的，通常反复出现，没有持久的免疫力表明先天免疫防御的重要性。寄生虫的主要细胞表面糖缀合物的分离和纯化，即阴道（TV）脂肪磷酸聚糖（LPG），使我们能够研究寄生虫与复杂阴道环境之间的新分子相互作用。 LPG是一种糖基磷脂酰肌醇样锚固分子，与其他类似GPI的寄生虫分子不同，它不含甘露糖，并且具有多n-乙酰乳糖胺的重复序列。我们是第一个表明液化石油气在寄生虫粘附和对正常人类阴道上皮细胞的信号中起关键作用的人。我们最新的新颖发现表明，LPG结合了阴道上皮细胞表达的甲状腺蛋白，并可能与针对细菌性阴道病（BV）的选定阴道微生物成分协同作用，该疾病已知，这是一种增加对HIV感染的易感性的疾病。我们已经将LPG的结构结构域（神经酰胺磷脂酰氨基醇 - 糖酸酯核心（CPI-GC））鉴定为M/Z 8695.5，是负责阴道和宫颈上皮细胞促炎激活的潜在甘肠蛋白配体。我们假设阴道lpg，尤其是其PI-GC，通过结合乳肠蛋白在生殖器粘膜和宿主免疫系统中具有相反的功能来调节宿主免疫炎症环境，并且可以通过BV相关的微弗洛拉来促进这些事件。为了检验这一假设，我们建议使用生理相关的体外模型系统，并将我们的实验发现与前瞻性收集的具有和没有BV的妇女队列的免疫反应相关联，并在感染TV和HIV-1之前和之后。我们的具体目的是：1）在正常和BV相关的微弗洛拉的背景下，定义了阴道lpg的阴道免疫调节剂和宿主受体的作用，并确定在子宫阴道阴道上皮细胞中工作的相关信号通路； 2）进一步阐明LPG的生化结构和负责乳肠蛋白结合和信号传导的CPI-GC子域； 3）确定并验证并验证并发性毛淋巴结病和细菌性阴道病的阴道免疫改变的分子模式，这些模式可能会增加HIV感染的风险。拟议的研究将扩大阴道T.阴道逃避免疫逃避的理解。它将阐明HIV-1与毛诺病和BV的关系增加的机制，验证阴道免疫失调的诊断和预后生物标志物，并为新的预防和治疗策略铺平道路。公共卫生相关性：阴道滴虫是世界上最常见的非病毒性传播感染（trichomoniasis）之一，使妇女容易使妇女受到HIV-1感染，早产和癌症的影响；全球超过1.8亿人，包括8-1亿美国人每年被感染。随着对寄生虫的抗生素抗性，基于分子医学进步的新型预防策略的发展至关重要。这项研究的目的标题为“与炎症后遗症相关的分子链球菌 - 宿主相互作用”是揭示与炎症症状和感染易感性相关的寄生虫 - 宿主相互作用的分子机制。