Trichomonas Lipophosphoglycan in Regulation Immune Responses

描述（由申请人提供）：T。阴道炎是世界上最常见的非病毒性性传播感染（滴虫病）之一。滴虫病与早产、低出生体重、宫颈癌、HIV-1传播和阴道炎的发病率增加有关，可能是通过诱导炎症细胞因子和生殖道粘膜中的免疫调节相互作用知之甚少。目前还不清楚为什么几乎一半的妇女诊断为滴虫病是无症状的，而另一半发展的症状严重的炎症反应。我们已经分离，纯化和部分特点脂磷酸聚糖（LPG），寄生虫的主要细胞表面糖缀合物，这使我们能够在分子水平上研究宿主-寄生虫相互作用。初步研究结果表明，T.阴道炎（TV）LPG介导寄生虫对人阴道上皮细胞的粘附，并刺激代表女性下生殖道粘膜的人单核细胞和鳞状上皮细胞类型中趋化因子的诱导。我们的结果还表明，阴道和宫颈上皮细胞中诱导的趋化因子独立于细胞损伤释放的细胞因子。我们推测TV LPG通过生殖道上皮细胞上的受体信号传导触发粘膜炎症反应。所提出的机制涉及NF-κ B活化、细胞因子和趋化因子的上调以及上皮免疫调节途径的调节。我们建议通过以下具体目标来检验我们的假设：（1）表征对TV LPG的旁分泌反应，包括细胞因子/趋化因子的产生和在人阴道、子宫颈外和子宫颈内上皮细胞中起作用的途径，（2）确定这些作用是否通过Toll受体介导，和（3）LPG分子的什么结构域是引发和维持或抑制这些炎症反应所必需的。这项研究将扩大对T.并且可以提供用于临床验证的潜在诊断和预后疾病标志物。由拟议的研究确定的宿主反应途径可能会转化为未来的临床研究，涉及生殖失败，癌症和与滴虫病相关的HIV-1感染易感性的机制，并可能有助于开发新的疫苗和药物靶点，以预防和治疗T。迷走神经感染和并发症。

DESCRIPTION (provided by applicant): T. vaginalis is one of the most common non-viral sexually transmitted infections (trichomoniasis) in the world. Trichomoniasis has been linked to increased incidence of pre-term delivery, low birth weight, cervical cancer, HIV-1 transmission and vaginitis possibly via induction of inflammatory cytokines and poorly understood immunoregulatory interactions in the reproductive tract mucosa. It is unclear why almost half of the women diagnosed with trichomoniasis are asymptomatic while the other half develops symptoms of severe inflammatory reaction. We have isolated, purified and partially characterized lipophosphoglycan (LPG), the main cell surface glycoconjugate of the parasite, which has enabled us to study host-parasite interactions at the molecular level. The results from our initial investigations demonstrate that T. vaginalis (TV) LPG mediates the adhesion of parasites to human vaginal epithelial cells and stimulates the induction of chemokines in human monocytes and squamous epithelial cell types representing the lower female genital tract mucosa. Our results also demonstrate that chemokines are induced in vaginal and cervical epithelial cells independently of cytokines released by cell damage. We hypothesize that TV LPG triggers the mucosal inflammatory reaction by signaling via receptors on the reproductive tract epithelial cells. The proposed mechanism involves NF-KB activation, upregulation of cytokines and chemokines and modulation of epithelial immunoregulatory pathways. We propose to test our hypothesis by the following specific aims: (1) characterize paracrine responses to TV LPG, including production of cytokines/chemokines and pathways operating in the human vaginal, ectocervical and endocervical epithelial cells, (2) determine whether these effects are mediated through Toll receptors, and (3) what domain(s) of the LPG molecule are required for initiating and sustaining or suppressing these inflammatory responses. The proposed research will expand the understanding of the immune evasion mechanisms exploited by T. vaginalis and may provide potential diagnostic and prognostic disease markers for clinical validation. Host response pathways identified by the proposed research may be translated into future clinical studies on mechanisms underlying reproductive failure, cancer and susceptibility to HIV-1 infection associated with trichomoniasis and may assist the development of new vaccine and drug targets to prevent and cure T. vaginalis infections and complications.