HCA_Gut_Henry_Dale_Fellowship_RNA_mouse

Whipworms infect hundreds of millions of people causing trichuriasis, a major neglected disease. Whipworms are large metazoan parasites that inhabit a multi-intracellular niche within their host caecal epithelia, where they manipulate mucosal physiology and inflammation through interactions with the intestinal epithelial cells and stem cell niche. These interactions enable chronic infections where whipworms are tolerated for years; but at a mechanistic level, how they operate is not understood. This research aims to define these interactions and bring a mechanistic understanding to how they underpin whipworm invasion, colonisation and persistence in their mucosal niche. This work will build upon a novel model using caecal organoids (termed caecaloids), the first to reproduce whipworm infections in vitro, to address two fundamental aims. First, to determine how whipworms invade and colonise intestinal epithelia using imaging and transcriptomic analyses of infected caecaloids. Second, to define how whipworms impact stem cell niche remodelling to promote their persistence using microscopy, FACS and transcriptomics of infected caecaloids and chronically-infected mice. This research will transform our understanding of the whipworm mucosal niche potentially yielding new targets for anti-parasitic therapies, and provide novel insights into how the intestinal epithelia repairs damage with relevant application toward intestinal inflammatory diseases.