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

只有在我们越来越深入地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。最近的观察导致了几个宿主蛋白家族的发现，称为模式识别分子，包括Toll样受体和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宿主细胞的生理变化，表明它们在调节抗微生物免疫方面发挥着关键作用。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，这些病原体导致随后产生长期免疫反应。在我概述的项目中，我将特别致力于描述导致NOD样受体触发的2型免疫反应的免疫级联反应，并剖析参与诱导这一免疫效应臂的可溶性介质。我将(I)确定IL-4和IL-13在Nod1和Nod2介导的病原体识别中的先天来源(S)，并研究IL-25和IL-33在2型免疫启动中的作用；(Ii)研究Nod1和Nod2驱动的2型免疫在体内胃肠道感染模型中的保护作用；(Iii)研究干细胞因子介导的c-kit信号在Nod1和Nod2介导的免疫应答中的作用。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，这将使我们能够量身定做预防性疫苗接种战略，以抗击传染病。

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.