Whipworms (Trichuris trichiura) are soil-transmitted helminths that infect approximately 600 - 800 million people globally and cause Trichuriasis, a major neglected tropical disease. The parasitic worms penetrate the caecal epithelium where they mature and establish as adults, resulting in a host immune response that can cause disease. Initial stages of larval infection are thought to be crucial in determining whether the parasite is expulsed or whether it remains in the gut causing severe intestinal inflammation. Development of new therapeutics to prevent and/or eradicate whipworm infections rely on understanding early infection stages of the parasitic worm. The murine parasite (Trichuris muris) is currently used as a mouse model of human T. trichiura infection, and is the main tool of Trichuriasis research.
Why we funded it
This David Sainsbury Fellowship aims to replace the need for animal models in studying the interactions between gut epithelia and the murine infective T. muris whipworm by using a three dimensional (3D) “mini-gut” organoid culture method.
One of the major drawbacks in Trichuriasis research is the dependency on the use of animal models as currently T. trichiura cannot be maintained in culture in the laboratory. Approximately 6-8 mice per group are used in a typical experiment analysing Trichuriasis, whilst large screens seeking to link infection phenotypes to host genetics require a further 1,500 mice per year. Using the 3D mini-gut organoid will allow Dr Duque Correa and colleagues at the Wellcome Trust Sanger Institute, to replace all animals needed for Trichuriasis studies.
3D mini-gut organoids are in vitro cellular clusters derived from primary stem cells, capable of both self-renewal and organisation. Dr Duque Correa has developed a microinjection method for delivering fluorescently labelled T. muris larvae directly into the lumen of the organoids. Through this fellowship Dr Duque Correa aims to optimise this method and evaluate the response of the organoid to the whipworm larvae infection. This will allow visualisation of the early whipworm larvae colonisation and determine which specific intestinal epithelial cell is targeted by the larva. Dr Duque Correa also aims to pilot the use of human organoids as a T. trichiura infection model to translate the findings from the murine organoids.
Duque-Correa MA et al. (2022). Defining the early stages of intestinal colonisation by whipworms. Nature Communications 13: e1725. doi: 10.1038/s41467-022-29334-0
Mkandawire TT et al. (2022). Hatching of parasitic nematode eggs: a crucial step determining infection. Trends in Parasitology 38(2): 174–87. doi: 10.1016/j.pt.2021.08.008
Duque-Correa MA et al. (2020). Development of caecaloids to study host-pathogen interactions: new insights into immunoregulatory functions of Trichuris muris extracellular vesicles in the caecum. International Journal of Parasitology 50(9): 707-718. doi: 10.1016/j.ijpara.2020.06.001
Duque-Correa MA et al. (2020). Organoids – New Models for Host–Helminth Interactions. Trends in Parasitology 36(2):170-181.doi:10.1016/j.pt.2019.10.013