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

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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