Authors

M Duque-Correa¹;  ¹ University of Cambridge, UK

Discussion

Whipworms (Trichuris spp) are large metazoan parasites that inhabit multi-intracellular epithelial tunnels in the caecum and proximal colon of their hosts, causing chronic disease in humans and other mammals. Whipworms 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. Our research aims to define these interactions and bring a mechanistic understanding to how they underpin whipworm invasion, colonisation, and persistence in their mucosal niche. To address this aim, we have established a model that for the first time effectively reproduces whipworm (Trichuris muris) infection in vitro using caecal organoids (caecaloids) and combined it with in vivo infections and imaging and transcriptomic analysis. Utilising these models, we have shown that T. muris first-stage (L1) larvae degrade mucus layers to access epithelial cells and have visualised “live” the invasion of IECs and the formation of syncytial tunnels. In early syncytial tunnels, larvae are completely intracellular, woven through multiple live dividing cells. Moreover, using single-cell RNA sequencing, we revealed that progression of infection results in cell damage and an expansion of enterocytes expressing of Isg15, potentially instigating the host immune response to the whipworm and tissue repair. Excitingly, we have recently observed larval development from early to late stages inside syncytial tunnels in caecaloids akin to those seen in vivo. Further, we are currently working towards translating this system to human organoids and the human whipworm (T. trichiura). Caecaloids have unlocked new opportunities to study whipworm developmental and biology, while reducing the number of animals required for these studies. Collectively, our research is unravelling intestinal epithelium invasion by whipworms and revealing specific host-parasite interactions that allow the whipworm to establish and persist in its multi-intracellular niche.