INNATE IMMUNE RESPONSES TO MALARIA PARASITE

描述(由申请人提供)：为应对恶性疟原虫感染而产生的促炎介质导致严重疟疾。然而，人们对这些免疫反应的激发和调控机制知之甚少。糖基磷脂酰肌醇(GPI)被认为是导致疟疾发病的主要寄生虫因子。先前，我们发现GPI诱导的巨噬细胞活化主要是由TLR2通过激活依赖于MyD88的MAPK和NF-KB途径来实现的，这两个途径在促炎介质的产生中起着不同的作用。由于GPI是膜结合的，在裂殖体爆发期间不会释放，这会产生峰值水平的 对于促炎反应，重要的是研究作为免疫系统靶标的生理上相关的寄生虫成分，关于宿主受体特异性和天然免疫反应的受体依赖的调节。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，树突状细胞在启动和调节天然免疫中发挥着关键作用。在前期工作的基础上，我们提出了以下具体目标：(1)研究ERK对GPI诱导的IL-6和IL-12产生的调节失调的机制，以及识别GPI所需的TLR1或TLR6。(2)研究巨噬细胞和DC对寄生虫裂殖体释放成分的促炎反应中的受体特异性，以及DC对T细胞反应的激活。(3)确定伯氏疟原虫的受体特异性是否反映了恶性疟原虫主要TLR配体的受体特异性。(4)研究疟疾原虫诱导的耐受性，包括巨噬细胞和DC从促炎反应到抗炎反应的转换，以及DC对T细胞反应的调节。总体目标是深入了解疟疾寄生虫的细胞信号机制和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的机制，并利用这一知识为治疗带来好处。 疟疾是世界各地的一项重大公共卫生危机，影响到约40%的人口，并导致2人死亡。 每年有300万人。目前，由于抗药性，疟疾正在迅速传播。来自非疟疾地区的大量人(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，他们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/治疗和/或疫苗。本申请中提议的研究所获得的知识应被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.