INNATE IMMUNE RESPONSES TO MALARIA PARASITE

描述（由申请人提供）：恶性疟原虫感染后产生的促炎介质导致严重疟疾。然而，很少有人知道的机制，这些免疫反应引起和调节。糖基磷脂酰肌醇（GPIs）被认为是疟疾致病的主要寄生虫因子。以前，我们发现GPI诱导的巨噬细胞活化主要由TLR 2介导，通过激活MyD 88依赖性MAPK和NF-κ B途径，其差异有助于促炎介质的产生。由于GPIs是膜结合的，在线粒体爆发期间不会释放，这会产生峰值水平的 在促炎反应中，重要的是研究生理学相关的寄生虫组分，其是关于宿主受体特异性和先天性免疫反应的受体依赖性调节的免疫系统的靶标。此外，很少或没有关于树突状细胞（DC）识别寄生虫的受体特异性的信息，树突状细胞在先天免疫的启动和调节中起关键作用。本研究在前期工作的基础上，提出以下具体目标：（1）研究GPIs诱导的IL-6和IL-12产生的ERK依赖性失调机制，并探讨GPIs对TLR 1或TLR 6的识别需求。(2)研究巨噬细胞和树突状细胞对寄生虫释放成分的促炎反应的受体特异性，以及树突状细胞对T细胞反应的激活作用。(3)在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)研究疟原虫诱导的耐受性，包括巨噬细胞和树突状细胞从促炎反应向抗炎反应的转换，以及树突状细胞对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原虫的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，并利用这些知识进行治疗。 疟疾是世界上一个主要的公共卫生危机，影响到约40%的人口，造成2- 每年300万人。目前，由于抗药性，疟疾正在迅速蔓延。来自非疟疾地区的许多人（军事和商业人员、外交官和游客）也面临更大的风险，由于他们的非免疫状态，特别容易受到严重甚至致命形式的疾病的影响。因此，迫切需要新的药物/治疗剂和/或疫苗。这项申请中提议的研究所获得的知识应证明对防治疟疾很有价值。

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.