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

哺乳动物的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(CLR)是一个古老的模式识别受体(PRR)家族，参与病原体的识别和适当免疫反应的启动和形成。寄生虫仍然感染着全球约20亿人，并已进化出复杂的机制，通过主动调节宿主免疫系统来避免它们被免疫驱动的消除。本研究旨在研究巨噬细胞诱导的CLR(MINCLE)在拉蒂圆线虫感染(一种人类钩虫感染模型)中的作用，重点是蠕虫诱导的免疫调节。它汇集了Lepenies实验室在CLR生物化学方面的专业知识和Breloer实验室在蠕虫免疫学和蠕虫诱导的免疫调节方面的专业知识。在初步实验中，我们记录了S.Ratti裂解物对MINCLE的结合和激活，从而表明存在激动型MINCLE配体。拉蒂沙门氏菌衍生的配体与MINCLE的结合具有生物学意义，因为在拉蒂沙门氏菌感染期间，MINCLE缺陷小鼠表现出肠道寄生虫负担减少，同时伴随着2型相关细胞因子的产生增加。因此，拉蒂沙门氏菌衍生产物的MINCLE参与可能被用来调节有效驱除寄生虫所需的适当的2型免疫反应。缺乏CARD9的小鼠，一种参与MINCLE介导的信号转导的适配器分子，表现出MINCLE缺陷的小鼠，进一步支持了这一假说。虽然几个小组在真菌和原生寄生虫感染期间显示了MINCLE的免疫调节功能，但对于MINCLE在蠕虫感染中的作用还缺乏了解。在这个建议中，我们打算使用Lepenies实验室已经建立的方法，在分子水平上鉴定蠕虫来源的MINCLE配体。利用Breloer实验室建立的S.Ratti感染模型，我们的目标是识别由MINLCE介导的信号调节的免疫效应器。通过分析蠕虫来源的MINCLE配体在体外激活APC的刺激能力和激活状态，我们试图阐明其潜在的分子机制。综上所述，我们期望通过MINCLE的参与来揭开一条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.