Role of the C-type lectin receptor MINCLE in Strongyloides ratti recognition and anti-helminth immune responses

哺乳动物免疫系统保护我们免受过多不同病原体的感染，这些病原体需要定制的免疫效应细胞组合才能有效控制。C型凝集素受体（C-type lectin receptor，C-type Lectin receptor，C-type Lectin receptor）代表模式识别受体（pattern recognition receptor，PRR）的一个古老家族，并且参与病原体的识别以及适当免疫应答的启动和形成。蠕虫寄生虫仍然感染ca。本研究旨在探讨巨噬细胞诱导型蠕虫（Macrophage-inducible nucleotide，MINCLE）在钩虫感染（人体钩虫感染模型）过程中的作用，重点研究蠕虫诱导的免疫调节。它汇集了Lepenies实验室关于蠕虫生物化学和Breloer实验室关于蠕虫免疫学和蠕虫诱导的免疫调节的专业知识。在初步实验中，我们记录了MINCLE与S. ratti裂解物，从而表明存在激动性MINCLE配体。S的结合。大鼠源性MINCLE配体具有生物学相关性，因为MINCLE缺陷小鼠在S.感染ratti。因此，S的MINCLE参与。鼠源性产物可用于调节有效驱除寄生虫所需的适当的2型免疫应答。这一假设进一步受到缺乏CARD 9的小鼠的事实的鼓励，CARD 9是一种参与MINCLE介导的信号传导的衔接分子，表型模仿MINCLE缺陷小鼠。虽然MINCLE的免疫调节功能，在真菌和原生生物寄生虫感染的几个群体中，有一个空白的知识关于MINCLE的作用蠕虫infecties.Within这个建议，我们打算确定蠕虫衍生的MINCLE配体的分子水平上，使用已经建立在Lepenies实验室的方法。采用S.在Breloer实验室建立的ratti感染模型中，我们的目标是鉴定由MINLCE介导的信号转导调节的免疫效应子。分析的刺激能力和激活状态的APC，将被激活的蠕虫衍生的MINCLE配体在体外的存在下，我们打算阐明潜在的分子机制。总之，我们希望通过MINCLE的参与来解开蠕虫介导的免疫逃避的新途径。

The mammalian immune system protects us against infections with a plethora of different pathogens that require a customized combination of immune effector cells to be efficiently controlled. C-type lectin receptors (CLR) represent an ancient family of pattern recognition receptors (PRR) and are involved in both, the recognition of pathogens and the initiation and shaping of appropriate immune responses. Helminth parasites still infect ca. 2 billion humans worldwide and have evolved sophisticated mechanisms to avoid their immune-driven elimination by active modulation of their host immune system.This proposal intends to investigate the role of the Macrophage-inducible CLR (MINCLE) during Strongyloides ratti infection (a model of human hookworm infection), focusing on helminth-induced immune modulation. It brings together the expertise of the Lepenies laboratory regarding CLR biochemistry and the Breloer laboratory regarding helminth immunology and helminth-induced immune modulation. In preliminary experiments, we recorded binding and activation of MINCLE by S. ratti lysate, thus indicating the presence of agonistic MINCLE ligands. Binding of S. ratti-derived ligands to MINCLE was biologically relevant since MINCLE-deficient mice displayed a decreased intestinal parasite burden accompanied by an increased production of type 2 associated cytokines during S. ratti infection. Thus, MINCLE engagement by S. ratti-derived products may be exploited to modulate the appropriate type 2 immune responses needed for efficient parasite expulsion. This hypothesis is further encouraged by the fact that mice lacking CARD9, an adaptor molecule that is involved in MINCLE-mediated signalling, phenocopied MINCLE-deficient mice. While immune modulating functions for MINCLE were shown by several groups during fungal and protist parasite infection, there is a gap of knowledge regarding the role of MINCLE during helminth infections.Within this proposal, we intend to identify helminth-derived MINCLE ligands on a molecular level, using a methodology already established in the Lepenies laboratory. Employing the S. ratti infection model established in the Breloer laboratory, we aim to identify the immune effectors that are modulated by MINLCE-mediated signalling. Analysing the stimulatory capacity and the activation status of APC that will be activated in the presence of helminth-derived MINCLE ligands in vitro, we intend to elucidate the underlying molecular mechanisms. In summary, we expect to unravel a novel pathway of helminth-mediated immune evasion via engagement of MINCLE.