Innate Immune Receptors for Toxoplasma gondii

描述（由申请人提供）：Toll样受体（TLR）是先天免疫系统识别并快速响应微生物的主要手段。采用弓形虫病小鼠模型的研究表明，髓样分化因子88（MyD 88），TLR的衔接子信号分子，对于启动早期炎症反应和宿主抵抗弓形虫感染至关重要。刚地。至少有三种TLR（即TLR 2、TLR 4和TLR 11）参与T.小鼠弓形虫感染。人TLR 11有一个终止密码子，使这种蛋白质明显无功能。 我们的项目的主要目标是描述人类先天免疫系统对T.刚地。具体来说，我们将测试的假设，在人类中，TLR是关键的同源受体参与先天性免疫反应T。弓形虫速殖子影响细胞免疫的发展，TLRs相关分子的多态性影响人类对弓形虫的易感性。弓形虫感染我们将表征速殖子的能力，包括其糖基磷脂酰肌醇（GPI）和糖基肌醇磷脂（GIPL）或其他糖脂，通过脂质组学方法确定，通过TLR结合和信号人类细胞。我们将重点关注TLR 2和TLR 4。使用单核苷酸多态性（SNP），我们将寻找编码相关TLR的基因中的等位基因变异，以及对TLR触发的功能至关重要的信号通路中的蛋白质。为了确定是否与T.为了研究人类弓形虫感染的情况，我们将对先天性弓形虫病患者及其父母，以及稳定或频繁复发的眼部弓形虫病患者的TLR进行鉴定。我们还将评估TLR基因的等位基因变异是否影响T引起的先天和获得性免疫反应。无症状的弓形虫病以及先天性疾病患者或获得性眼弓形虫病。T.弓形虫在先天性感染个体中引起眼病和神经系统损伤;此外，它影响免疫功能低下的人，并且在获得弓形虫的人中的一部分人中引起眼病。出生后感染弓形虫。 确定参与寄生虫识别和影响T.弓形虫感染将提供关于新策略的重要信息，所述新策略可应用于人类弓形虫病的疫苗开发和治疗，所述疫苗和治疗可用于控制寄生虫传播、减轻上述病理并改善疾病的预后。

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.