INNATE IMMUNE RESPONSES TO MALARIA PARASITE

对疟疾寄生虫的先天免疫反应

基本信息

批准号：
8069834
负责人：
CHANNE D GOWDA
金额：
$ 35.07万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-01-15 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8069834
关键词：
1,2-diacylglycerol Abbreviations Acetylglucosamine Affect Anti-Inflammatory Agents Anti-inflammatory Antibody Formation Binding Bone Marrow Businesses Cell Nucleus Cell physiology Complex Dendritic Cells Dendritic cell activation Development Diglycerides Dimerization Disease Drug resistance EMSA Electrophoretic Mobility Shift Assay Erythrocytes GPI Membrane Anchors Galactosamine Gene Expression Genetic Glucosamine Glycosylphosphatidylinositols Goals Grant Green Fluorescent Proteins Human Human Resources IRAK1 gene Immune response Immune system Immunity Immunotherapeutic agent Infection Infection Control Inflammation Mediators Inflammatory Response Interleukin-1 Interleukin-10 Interleukin-12 Interleukin-4 Interleukin-6 Intravenous Knock-out Knowledge Learning Ligands MAP Kinase Gene MAP Kinase Kinase Kinase MAP3K7 gene MAP3K8 gene MAPK3 gene MAPK8 gene Macrophage Activation Malaria Malaria Vaccines Mannose Manuscripts Marrow Mediating Mediator of activation protein Membrane Military Personnel Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Modeling Mus Myelogenous Natural Immunity Ovalbumin Parasitemia Parasites Pathogenesis Pathway interactions Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phosphatidylinositols Phosphotransferases Plasmodium falciparum Play Population Production Protein Family Protein Kinase C Protein Tyrosine Kinase Public Health Regulation Reporting Research Personnel Risk Rodent Role Signal Pathway Signal Transduction Single Nucleotide Polymorphism Specificity Staging Stimulus Structure Structure-Activity Relationship T cell response T-Cell Activation TLR1 gene TLR2 gene TLR4 gene TLR6 gene TNF Receptor-Associated Factors TNFRSF5 gene Therapeutic Toll-like receptors Up-Regulation Vaccines Vacuole Validation Work adapter protein adaptive immunity combat cytokine glycoprotein phospholipase D hemozoin human NOS2A protein in vivo killings knockout gene macrophage man monocyte mortality novel phosphoethanolamine receptor receptor function response small hairpin RNA stress-activated protein kinase 1

项目摘要

DESCRIPTION (provided by applicant): Pro-inflammatory mediators produced in response to Plasmodium falciparum infection contribute to severe malaria. However, very little is known about the mechanism by which these immune responses are elicited and are regulated. The glycosylphosphatidylinositols (GPIs) have been proposed as the major parasite factors that contribute to malaria pathogenesis. Previously, we showed that GPI-induced activation of macrophages is mediated mainly by TLR2 via the activation of the MyD88-dependent MAPK and NF-KB pathways, which differentially contribute to the production of pro-inflammatory mediators. Since GPIs are membrane bound and are not released during schizont burst, which produces peak levels of pro-inflammatory responses, it is important to study the physiologically relevant parasite components that are the targets of the immune system with regard to the host receptor specificity and receptor-dependent modulation of innate immune responses. Further, little or no information is available on the receptor specificity in the recognition of parasites by dendritic cells (DCs), which play crucial role in the initiation and modulation of innate immunity. Extending the work done during the previous grant period, we propose the following Specific Aims: (1) To study the mechanism of ERK-dependent dysregulation of GPI-induced IL-6 and IL-12 production and to investigate the requirement of TLR1 or TLR6 for recognition of GPIs.(2) To investigate the receptor specificity in the pro-inflammatory responses to parasite schizont-released components in macrophages and DCs, and activation of T cell responses by DCs. (3) To determine in vivo whether the receptor specificity of P. berghei mirrors the ligand-receptor specificity observed for the major TLR ligands of P. falciparum. (4) To study the malaria parasite-induced tolerance with regard to switching from pro- to anti-inflammatory responses by macrophages and DCs, and the modulation of T cell responses by DCs. The overall goal is to gain in-depth understanding of the mechanisms of cell signaling and regulation of innate immune responses to malaria parasite. The long-term objectives of this project are to understand in detail the mechanisms of innate immune responses to P. falciparum infection and to use this knowledge for therapeutic benefit. Malaria is a major public health crisis around the world, affecting ~40% of the population and killing 2- 3 million people annually. Currently, malaria is spreading rapidly due to drug resistance. A large number of people from non-malaria regions (military and business personnel, diplomats and visitors) are also at increased risk and are particularly more vulnerable to severe or even fatal forms of the disease because of their non-immune status. Therefore, novel drugs/therapeutic and/or vaccine are needed urgently. The knowledge gained by the studies proposed in this application should prove valuable in combating malaria.

描述（由申请人提供）：恶性疟原虫感染产生的促炎介质会导致严重的疟疾。然而，人们对引发和调节这些免疫反应的机制知之甚少。糖基磷脂酰肌醇（GPI）已被认为是导致疟疾发病的主要寄生虫因子。此前，我们发现 GPI 诱导的巨噬细胞激活主要由 TLR2 通过激活 MyD88 依赖性 MAPK 和 NF-KB 途径介导，这对促炎介质的产生有不同的贡献。由于 GPI 是膜结合的，并且在裂殖体爆发期间不会释放，从而产生峰值水平促炎症反应，重要的是研究生理相关的寄生虫成分，这些成分是免疫系统在宿主受体特异性和先天免疫反应的受体依赖性调节方面的目标。此外，关于树突状细胞（DC）识别寄生虫的受体特异性的信息很少或根本没有，而树突状细胞在先天免疫的启动和调节中发挥着至关重要的作用。延续上一资助期间所做的工作，我们提出以下具体目标：(1) 研究 GPI 诱导的 IL-6 和 IL-12 产生的 ERK 依赖性失调机制，并研究 TLR1 或 TLR6 的需求(2)研究巨噬细胞和树突状细胞中对寄生虫裂殖体释放成分的促炎反应中受体的特异性，以及树突状细胞对T细胞反应的激活。 (3) 体内确定伯氏疟原虫的受体特异性是否反映了针对恶性疟原虫的主要 TLR 配体观察到的配体-受体特异性。 (4) 研究疟原虫诱导的巨噬细胞和 DC 从促炎反应转变为抗炎反应的耐受性，以及 DC 对 T 细胞反应的调节。总体目标是深入了解细胞信号传导机制和对疟疾寄生虫先天免疫反应的调节。该项目的长期目标是详细了解恶性疟原虫感染的先天免疫反应机制，并利用这些知识获得治疗益处。疟疾是世界范围内的一项重大公共卫生危机，影响约 40% 的人口，并导致 2 人死亡每年300万人。目前，由于耐药性，疟疾正在迅速蔓延。来自非疟疾地区的大量人员（军事和商业人员、外交官和游客）也面临更大的风险，并且由于他们没有免疫力，特别容易感染严重甚至致命的疾病。因此，迫切需要新的药物/治疗方法和/或疫苗。通过本申请中提出的研究获得的知识在对抗疟疾方面应该是有价值的。