Innate Immune Receptors for Toxoplasma gondii

弓形虫先天免疫受体

• 批准号: 7152613
• 负责人: RICARDO TOSTES GAZZINELLI
• 金额: $ 46.8万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7152613
• 关键词: Toxoplasma gondii; clinical research; genes; glycolipids; human; immune response; immune system; immunologic receptors; infection; lipids; proteins; toxoplasmosis

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.

描述（由申请人提供）：Toll样受体（TLR）是先天免疫系统识别并迅速响应微生物的主要均值。采用弓形虫病小鼠模型的研究表明，髓样分化因子88（MyD88）是TLR的适应器信号分子，对于启动早期炎症反应和对T. gondii感染的敌人抗性至关重要。在小鼠中，至少三个TLR（即TLR2，TLR4和TLR11）参与了先天免疫系统的激活和宿主抗性。人类TLR 11具有终止密码子，使该蛋白质显然非功能。 我们项目的主要目标是表征机制，使人类先天免疫系统对T. gondii的感染做出反应。具体而言，我们将检验以下假设：在人类中，TLR是与gondii tachyzoites的先天免疫反应有关的关键同源受体，会影响细胞介导的免疫力的发展，并且在TLR中，与TLR相关分子的多态性会影响gondiii的人类易感性。感染。我们将表征速二氏菌的能力，包括其糖基磷脂酰肌醇（GPI）和糖基辛糖基辛磷脂（GIPL）或其他由Lipidomomic方法确定的，以通过TLR来结合并通过TLR结合人类细胞。我们的重点将放在TLR2和TLR4上。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信号通路中的蛋白质，这对于TLR触发的功能至关重要。为了确定是否由于人类的gondii而与疾病有关联，我们将表征先天性弓形虫病及其父母的患者的TLR，以及眼睛毒质量稳定或经常复发的眼毒性患者。我们还将评估TLR基因中的等位基因变异是否影响先天性和获得的免疫反应在无症状和先天性疾病患者中引起的免疫反应，还是获得了眼癌。 T. gondii会导致先天感染的个体的眼部疾病和神经系统损伤；另外，它会影响产后获得弓形虫的人的免疫功能低下的人和眼科疾病。 鉴定寄生虫识别涉及的先天免疫机制以及在弓形虫感染期间影响免疫反应的识别，将提供有关新策略的重要信息，这些信息可能适用于疫苗开发和人类弓形虫病的治疗上面提到的病理并改善了疾病的预后。