Title

Identifying the key determinants of intestinal epithelia invasion and colonisation by the parasitic worm Trichuris muris

Abstract

Whipworms (Trichuris trichiura) are gastrointestinal parasites that cause Trichuriasis, a major neglected tropical disease. 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 physical and molecular cues directing the larvae and mediating their penetration and colonisation of these cells are currently unknown. Interestingly, the mouse whipworm (T. muris) does not establish well in mice with reduced sulphated mucus (Sat1-/-). The aim of the project is to investigate the role of the mucus layer as molecular cues for the penetration and colonization of larvae in the IE by using use a novel T. muris caecal organoid model developed by the Duque-Correa lab. This model overcomes challenges of limited in situ accessibility to L1 larvae in vivo, which infect less than 1% of the IE. The student will grow organoids from WT and Sat1-/- mice and then infect the organoids with whipworm L1 larvae to: 1) evaluate the impact of reduced sulphated mucus on the rates of invasion of the IE by whipworm L1 larvae and 2) determine whether mucus serves as an energy supply for whipworm L1 larvae and if mucus chemical composition affects larval chemosensation and viability during colonisation of the IE.

Required Knowledge:

• Basic biology knowledge is expected. Prior laboratory experiences are beneficial but not essential.

Supervisors:

Day-to-day supervisor: Charlotte Tolley (ct628@cam.ac.uk)

Co-supervisor: María Adelaida Duque-Correa (mad75@cam.ac.uk)

Cambridge Stem Cell Institute - JCBC, Level 2