Intestinal organoids as a replacement strategy to unravel early host intestinal epithelia interactions with whipworms

Project Background

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.

Research Methods

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.

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Fellowship

Status:

Active

Principal investigator

Dr Maria Duque Correa

Institution

Wellcome Trust Sanger Institute

Grant reference number

NC/P001521/1

Award date:

Nov 2017 - Nov 2020

Grant amount

£251,248