Dissecting the spatial organisation of the innate immune response to parasitic helminth infection at the single cell level

鞭虫感染是人类寄生虫感染的三种主要类型之一，感染了世界上十五分之一的人口。我们已经使用小鼠鞭子虫（Trichuris muris）模型来定义对寄生线虫感染的抗性和易感性范例1,2，并因此确定了肠道疾病期间免疫和免疫调节的新机制3。当Trichuris卵在肠道微生物的刺激下孵化并侵入大肠上皮时，感染就开始了，引发以白细胞介素13为主或以干扰素y为主的免疫反应，分别导致耐药性或易感性。决定肠道局部产生哪种类型免疫反应的关键因素尚不清楚。该项目旨在描述这些因素的特征，重点是确定肠道组织内寄生虫入侵的精确解剖部位的重要性，以及已知控制不同效应和调节能力的肠道引流淋巴结中免疫反应的关键解剖部位。具体来说，我们将利用成像方法来时空映射不同的免疫细胞如何共同定位到寄生虫的近端，然后导航到特定的引流淋巴结来协调不同的保护性或病理性免疫反应。确定对Trichuris的先天和早期适应性反应的机制不仅会增加我们对这一重要病原体免疫的理解，而且有助于我们对粘膜免疫和免疫如何在屏障表面起作用的基本理解

Whipworm infection is one of the three major types of parasitic helminth infections of man, infecting one in fifteen of the world's population. We have used the murine model of whipworm (Trichuris muris) to define paradigms of resistance and susceptibility to parasitic nematode infection1,2 and as a consequence identified new mechanisms of immunity and immunoregulation during intestinal disease3. Infection proceeds when Trichuris eggs hatch under the stimulation of the intestinal microbiota4 and invades the epithelium of the large intestine initiating either an interleukin 13 dominated or interferon-y dominated immune response leading to resistance or susceptibility respectively. The key factors that determine which type of immune response is generated locally in the intestine are unknown. The project aims to characterise these factors with an emphasis on defining the importance of the precise anatomical site of parasite invasion within the intestinal tissue and the critical anatomical site of the immune response in the series of lymph nodes that drain the intestine that are known to control different effector and regulatory capacities. Specifically, we will utilise imaging approaches to spatiotemporally map how different immune cells co-localise proximal to the parasite and then navigate to specific draining lymph nodes to coordinate distinct protective or pathological immune responses. Defining the mechanisms underpinning the innate and early adaptive response to Trichuris will not only increase our understanding of immunity to this important group of pathogens but also contribute to our fundamental understanding of mucosal immunity and how immunity operates at barrier surfaces