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(MRC DTP) Innate immune crosstalk and orchestration of mucosal immunity


Project Description

Barrier tissue sites - including the gastrointestinal tract, lung and skin – are the primary site of exposure to a multitude of foreign organisms and environmental challenges. Within the intestine this includes the commensal microbiota – a complex community of trillions of mutualistic bacteria, which help to liberate critical nutrients from the diet and to regulate the host immune system. In turn the mucosal immune system plays critical roles in containing commensal bacteria within the intestine and suppressing potentially inflammatory responses, which have the potential to drive disease. Indeed, dysregulation of the intestinal immune system results in inappropriate responses to the commensal microflora that drive disease pathogenesis and chronic inflammation in Inflammatory Bowel Disease (IBD).

Thus, a network of immune interactions and crosstalk between tissue-resident immune cells is required to ensure regulatory and homeostatic interactions with the microbiota. We and others have previously demonstrated that populations of innate lymphoid cells (ILCs) act to reinforce barrier function and modulate the wider adaptive immune system in order to prevent inflammatory responses driven by the commensal microbiota (Hepworth et al Nature 2013, Hepworth et al Science 2015, Melo-Gonzalez et al J Exp Med 2019). These advances implicate ILCs as critical regulators of intestinal health and homeostatic host-commensal interactions, however the full extent to which these cells interact with and modulate other key players in the mucosal immune system remain poorly understood.

In this project the successful candidate will utilize a range of emerging technologies (mass cytometry and imaging (CyTOF/Hyperion), single cell and bulk RNA-sequencing and 16S sequencing) to comprehensively explore interactions between ILC subsets and classical members of the innate and adaptive immune cell lineages. Through unbiased and hypothesis-led approaches being developed within the lab, the candidate will explore novel interactions and cross-regulation by ILCs in both mucosal barrier tissue sites and associated lymphoid tissues and develop and utilize a range of transgenic animal models to explore the relevance and impact of these pathway in health and disease (including models of intestinal inflammation and infection).

The candidate will work within a supervisory team with a strong track record across a broad spectrum of mucosal immunology, microbiology and cell biology, and will be based in the Lydia Becker institute for Immunology and Inflammation, within the world-class Faculty of Biology, Medicine and Health (FBMH), with access to a wide range of core facilities and expertise from the supervisory team and the wider faculty.

https://www.bmh.manchester.ac.uk/research/domains/infection-immunity-inflammation-repair/immunology/
https://www.research.manchester.ac.uk/portal/matthew.hepworth.html
https://www.research.manchester.ac.uk/portal/andrew.macdonald.html

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 View Website

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

Sonnenberg G.F and Hepworth M.R.
Functional interactions between innate lymphoid cells and the adaptive immune system
Nature Reviews Immunology 2019

Hooper LV, Littman DR and MacPherson AJ.
Interactions between the microbiota and the immune system.
Science 2012 June 8; 336(6086)

Belkaid Y and Hand TW.
Role of the microbiota in immunity and inflammation.
Cell 2014 Mar 27; 157(1)

Cerovic V, Bain CC, Mowat AM, Milling SW
Intestinal macrophages and dendritic cells: what’s the difference?
Trends Immunol 2014 June;35(6): 270-7

Mortha A, Chudnovskiy A, Hashimoto D, Bogunovic M, Spencer SP, Belkaid Y, Merad M
Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis
Science 2014 Mar 28;343(6178):1249288

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