Defining the immune cascade leading to Nod-like receptor mediated Type 2 immune responses

只有在我们日益深入了解复杂的宿主防御机制的基础上，才能在控制传染病方面取得进展。最近的观察导致发现了几个宿主蛋白家族，称为模式识别分子，包括Toll样和Nod样受体家族。这些宿主防御蛋白特异性地检测病原体的分子模式以及感染诱导的受感染宿主细胞的生理变化，这表明它们在调节抗微生物免疫中的功能具有关键作用。 本项目的重点是破译哺乳动物免疫系统如何识别病原体的机制，从而导致随后的长期免疫反应的指令。在我概述的项目中，我将专门致力于表征导致Nod样受体触发的2型免疫应答的免疫级联反应，并剖析参与诱导这种免疫效应臂的可溶性介质。我将（i）定义Nod 1和Nod 2介导的病原体识别后IL-4和IL-13的先天来源，并检查IL-25和IL-33对引发2型免疫的参与，（ii）在体内胃肠道感染模型中研究Nod 1和Nod 2驱动的2型免疫的保护作用，和（iii）研究干细胞因子介导的c-kit信号传导在Nod 1和Nod 2介导的免疫应答中的参与。从拟议的研究计划中获得的科学见解将促进我们的医学和科学知识，这将使我们能够制定预防性疫苗接种策略，以对抗传染病。

Progress for the control of infectious diseases can only be achieved on the basis of our increasing insights into the complex host defence mechanisms. Recent observations have led to the discovery of several host protein families, referred to as pattern recognition molecules including the families of the Toll-like and Nod-like receptors. These host defence proteins specifically detect molecular patterns of pathogens as well as infection-induced physiological changes of infected host cells, suggesting a critical role for their function in regulating antimicrobial immunity. The present project focuses on deciphering the mechanisms of how the mammalian immune system recognizes pathogens leading to the subsequent instruction of long-lived immune responses. In my outlined project I will specifiically aim to charcaterize the immune cascade leading to Nod-like receptor triggered type 2 immune responses and to dissect the soluble mediators involved to induce this immune effector arm. I will (i) define the innate source(s) of IL-4 and IL-13 upon Nod1- and Nod2-mediated pathogen recognition, and examine the involvement of IL-25 and IL-33 for the priming of type 2 immunity, (ii) study the protective role of Nod1- and Nod2-driven type 2 immunity in a gastrointestinal infection model in vivo, and (iii) investigate the involvement of stem cell factor mediated c-kit signalling in Nod1- and Nod2-mediated immune responses. The scientific insights gained from the proposed research program will advance our medical and scientific knowledge, which will enable us to tailor preventive vaccination strategies to combat infectious diseases.