Trichomonas Lipophosphoglycan in Regulation Immune Responses

描述（由申请人提供）：阴道滴虫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传播和阴道炎的发生率增加有关，可能是通过诱导炎症细胞因子和对生殖道粘膜免疫调节相互作用知之甚少。目前尚不清楚为什么几乎一半被诊断患有滴虫病的妇女没有症状，而另一半则出现严重炎症反应的症状。我们已经分离、纯化和部分表征了脂磷聚糖（LPG），这是寄生虫的主要细胞表面糖缀合物，使我们能够在分子水平上研究宿主与寄生虫的相互作用。我们的初步研究结果表明，T. vaginalis (TV) LPG介导寄生虫对人阴道上皮细胞的粘附，并刺激趋化因子在人单核细胞和鳞状上皮细胞类型（代表下女性生殖道粘膜）中的诱导。我们的研究结果还表明，趋化因子在阴道和宫颈上皮细胞中被诱导，独立于细胞损伤释放的细胞因子。我们假设TV LPG通过生殖道上皮细胞上的受体信号触发粘膜炎症反应。提出的机制涉及NF-KB激活，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验证我们的假设：(1)表征对TV LPG的旁分泌反应，包括细胞因子/趋化因子的产生以及在人类阴道、宫颈外和宫颈内上皮细胞中运作的途径；(2)确定这些影响是否通过Toll受体介导；(3)启动、维持或抑制这些炎症反应需要LPG分子的哪个结构域。本研究将扩大对阴道梭菌免疫逃避机制的理解，并可能为临床验证提供潜在的诊断和预后疾病标志物。通过拟议的研究确定的宿主反应途径可能会转化为未来与滴虫病相关的生殖衰竭、癌症和HIV-1感染易感性机制的临床研究，并可能有助于开发新的疫苗和药物靶点，以预防和治疗阴道滴虫感染及其并发症。

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.