About the Project
Whipworm infection is one of the three major types of parasitic helminth infections of man, infecting one in fifteen of the world’s population. We have used the murine model of whipworm (Trichuris muris) to define paradigms of resistance and susceptibility to parasitic nematode infection1,2 and as a consequence identified new mechanisms of immunity and immunoregulation during intestinal disease3.
T. muris infection proceeds when Trichuris eggs hatch under the stimulation of the intestinal microbiota4 and invades the epithelium of the large intestine. This can initiate either an interleukin 13 dominated or interferon- dominated immune response, leading to resistance or susceptibility respectively. Crucially, the key factors that determine which type of immune response is generated during infection remain unknown. The project aims to characterise these factors with an emphasis on defining the importance of the precise anatomical site of parasite invasion within the intestinal tissue and the compartmentalised imprinting of the emergent immune response in the intestinal draining lymph nodes. Using the T. muris model system of divergent immune responses the project will utilise imaging mass cytometry together with flow cytometry and transcriptomic analysis to define the spatial organisation of key cell populations activated to produce alarmins at the intestinal site of infection and the subsequent cellular response in the specific lymph nodes that drain these areas. The importance of the key cells/factors identified will be tested functionally in vivo, using transgenic models. Defining the mechanisms underpinning the innate and early adaptive response to Trichuris will not only increase our understanding of immunity to this important group of pathogens but also contribute to our fundamental understanding of mucosal immunity and how immunity operates at barrier surfaces.
www.manchester.ac.uk/lydia-becker-institute
www.wellcome-matrix.org
www.immunophenotyping.org
Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
Funding Notes
This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships
As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.
References
1. Grencis RK, Humphreys NE, Bancroft AJ (2014) Immunity to gastrointestinal nematodes: mechanisms and myths. Immunological Reviews. 260, 183-205
2. Foth BJ, Tsai IJ, Reid AJ, Bancroft AJ, Nichol S, Tracey A, Holroyd N, Cotton JA, Stanley EJ, Zarowiecki M, Liu JZ, Huckvale T, Cooper PJ, Grencis RK, Berriman M (2014) Whipworm genome and dual-species transcriptome analyses provide molecular insights into an intimate host-parasite interaction. Nature Genetics. 46, 693-700.
3. Grencis RK. (2015) Immunity to helminths: resistance, regulation, and susceptibility to gastrointestinal nematodes. Annual Reviews in Immunology, 33, 201-25.
4. Hayes, K.S., Bancroft, A.J., Goldrick, M., Portsmouth, C., Roberts I.S.& Grencis, R.K. (2010) Exploitation of the intestinal microflora by the parasitic nematode Trichuris muris: microflora regulates macrofauna. Science. 328, 1391-4.
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