Studying the impact of parasitic worm infections on intestinal stem cell fate and differentiation

Summary

Whipworms infect hundreds of millions of people and cause trichuriasis, a major neglected disease. These large metazoan parasites inhabit a multi-intracellular niche within their host gut lining, where they can remain for years. Whipworm infection occurs upon ingestion of eggs that hatch in the caecum in a process mediated by the host microbiota.

Motile first-stage L1 larvae released from the eggs transverse the mucus layers and enter the intestinal epithelia (IE) at the base of the crypts of Lieberkühn. Our research has shown that whipworm L1 larvae invade intestinal stem, deep secretory and progenitor cells; however, the impact of the parasite on the stem cell fate and stem cell niche remodelling remains unknown.

To persist in their host for years, whipworms manipulate the IE renewal cycle (3-5 days) thus avoiding expulsion. Hence, we hypothesise that whipworms induce changes in stem cell division and differentiation, influencing IE architecture and composition.

Project aims

The aim of this PhD project is to define the effects of whipworm infection on the intestinal epithelial stem cell niche remodelling that enable chronic infections. 

To address this aim, you will use a novel organoid model developed by the Duque-Correa lab, the first to reproduce whipworm infection in vitro (PMIDs: 32659277, 35365634), together with a mouse model of infection with the natural mouse whipworm, Trichuris muris.

Using these models, you will characterise gene expression changes (using bulk, single-cell and spatial transcriptomics) of intestinal epithelial cells and stem cell niche populations across infection and after eradication of the parasite.

Stem cell remodelling pathways modulated by the parasite will be further studied using lineage tracing and confocal imaging, and stem and stromal cell function will be assessed using organoid assays.

Contact details

Dr Maria Duque-Correa - mad75@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD