Innate Immune Receptors for Toxoplasma gondii

描述(申请人提供)：Toll样受体(TLRs)是先天免疫系统识别微生物并对其做出快速反应的主要手段。利用弓形虫病小鼠模型的研究表明，髓样分化因子88(MyD88)是TLRs的接头信号分子，对于启动早期炎症反应和宿主对弓形虫感染的抵抗力至关重要。至少有三种TLRs(即TLR2、TLR4和TLR11)参与了弓形虫感染小鼠天然免疫系统的激活和宿主抵抗。人类TLR11有一个终止密码子，使该蛋白明显不起作用。 我们项目的主要目标是描述人类先天免疫系统对弓形虫感染做出反应的机制。具体地说，我们将测试以下假设：在人类中，TLRs是参与弓形虫速殖子天然免疫反应的关键同源受体，影响细胞免疫的发展，以及TLRs相关分子的多态影响人类对弓形虫感染的易感性。我们将描述速殖子，包括它们的糖基磷脂酰肌醇(GPI)和糖肌醇磷脂(GIPLs)或其他糖脂通过TLRs结合和信号传递人类细胞的能力。我们的重点将是TLR2和TLR4。利用单核苷酸多态(SNPs)，我们将寻找编码相关TLRs的基因以及信号通路中对TLRs触发功能至关重要的蛋白质的等位基因变异。为了确定是否与人类弓形虫引起的疾病有关，我们将对先天性弓形虫病患者及其父母，以及保持稳定或频繁复发的眼弓形虫病患者的TLRs进行特征分析。我们还将评估TLR基因的等位基因变异是否会影响弓形虫在无症状和先天性疾病或获得性眼弓形体病患者中引发的先天性和获得性免疫反应。弓形虫会对先天感染的人造成眼病和神经损害；此外，它还会影响免疫功能受损的人，以及一部分出生后感染弓形虫的人会患上眼病。 识别弓形虫感染过程中参与识别寄生虫和影响免疫应答的先天免疫机制，将为人类弓形虫病疫苗开发和治疗提供重要信息，以控制寄生虫传播，减轻上述病理变化，改善疾病预后。

DESCRIPTION (provided by applicant): Toll-Like Receptors (TLRs) are a primary mean whereby the innate immune system recognizes and rapidly responds to microbes. Studies employing the mouse models of toxoplasmosis indicate that the Myeloid Differentiation Factor 88 (MyD88), an adaptor-signaling molecule for the TLRs, is critical for initiation of early inflammatory responses and host resistance to infection with T. gondii. At least three TLRs (i.e. TLR2, TLR4 and TLR11) are involved in activation of the innate immune system and host resistance during T. gondii infection in mice. Human TLR 11 has a stop codon making this protein apparently nonfunctional. The main goal of our project is to characterize mechanisms whereby the human innate immune system responds to infection with T. gondii. Specifically, we will test the hypotheses that in humans, TLRs are key cognate receptors involved in the innate immune response to T. gondii tachyzoites, influence development of cell- mediated immunity, and that polymorphisms in TLRs related molecules affects human susceptibility to T. gondii infection. We will characterize the ability of tachyzoites, including their glycosylphospatidylinositol (GPI) and glycosylinositolphospholipids (GIPLs) or other glycolipids, as determined by a lipidomic approach, to bind and signal human cells via TLRs. Our focus will be on TLR2 and TLR4. Using single nucleotide polymorphisms (SNPs) we will look for allelic variation in the genes encoding the relevant TLRs as well as proteins in the signaling pathways that are critical for the functions triggered by TLRs. To determine whether there are associations with disease due to T. gondii in humans, we will characterize TLRs in patients with congenital toxoplasmosis and their parents, and in patients with ocular toxoplasmosis that remains stable or that recurs frequently. We will also evaluate whether allelic variations in TLR genes influence innate and acquired immunologic responses elicited by T. gondii in asymptomatic as well as patients with congenital disease, or acquired ocular toxoplasmosis. T. gondii causes eye disease and neurologic damage in congenitally infected individuals; in addition it affects immunocompromised persons and eye disease in a proportion of those who acquire T. gondii postnatally. Identification of the mechanisms of innate immunity involved in parasite recognition and that influence immune response during T. gondii infection will provide important information about new-strategies that may be applicable in vaccine development and therapy of human toxoplasmosis that maybe used to control parasite transmission, lessen the pathologies mentioned above and to improve the prognosis of the disease.