Role of the C-type lectin receptors SIGNR3, MICL and DCIR in the recognition of plasmodial ligands and their contribution to the pathogenesis of cerebral malaria

疟疾是全球传染病死亡的主要原因，每年造成2亿多临床病例和600.000多人死亡。一种致命的并发症是脑型疟疾，它会在受影响的患者中引起神经症状。伯氏疟原虫(PBA)感染易感小鼠是目前研究脑型疟疾发病机制的首选模型。虽然获得性免疫在脑型疟疾发生发展中的作用已经被非常详细地分析，但关于先天免疫在脑型疟疾诱发中的作用却知之甚少。到目前为止，大多数研究都集中在Toll样受体在这一过程中的作用。相比之下，几乎没有研究调查C型凝集素受体(CLR)是否以及如何影响疟疾的进程。CLRs属于凝集素家族，识别病毒、细菌、真菌和寄生虫等病原体上的碳水化合物结构，参与启动免疫反应。在自己的初步工作中，研究表明，CLR有助于识别疟原虫，并可能确实在脑型疟疾的发展中发挥关键作用。在拟议项目的第一部分，将对CLR SIGNR3的不同的原生物质配体进行鉴定和生化表征。在第二部分中，机制研究将揭示CLRs SIGNR3、MICL和DCIR如何影响脑型疟疾的进程。除了CLR缺陷小鼠的PBA感染外，还将产生混合骨髓嵌合体，以分析这些CLR在脑型疟疾发病机制中的作用。

Malaria is a major global cause of death from infectious diseases, resulting in more than 200 million clinical cases and more than 600.000 deaths per year. A fatal complication is cerebral malaria that causes neurological symptoms in affected patients. The infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is currently the model of choice to study the pathogenesis of cerebral malaria. Whereas the role of adaptive immunity in the development of cerebral malaria has been analyzed quite in detail, little is known about the contribution of innate immunity to cerebral malaria induction. To date, most studies have focused on the role of Toll-like receptors in this process. In contrast, almost no studies have investigated whether and how C-type lectin receptors (CLRs) affect the course of malaria. CLRs belong to a family of lectins that recognize carbohydrate structures on pathogens such as viruses, bacteria, fungi, and parasites, thus they are involved in the initiation of immune responses. In own preliminary work, it was shown that CLRs contribute to Plasmodium recognition and may indeed play essential roles in cerebral malaria development. In the first part of the proposed project, distinct plasmodial ligands of the CLR SIGNR3 will be identified and characterized biochemically. In the second part, mechanistic studies will reveal how the CLRs SIGNR3, MICL, and DCIR impact the course of cerebral malaria. In addition to PbA infection of CLR-deficient mouse lines, mixed bone marrow chimeras will be generated to analyze the function of these CLRs in the pathogenesis of cerebral malaria.