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Environmental control of dendritic cell activation and function during pulmonary type 2 inflammation


Project Description

Type 2 inflammation is a defining feature of infection with parasitic worms (helminths), as well as being responsible for widespread suffering in allergies. Although both of these conditions exert a devastating global impact and lack effective vaccines or refined therapeutics, basic knowledge of the key cell types and mediators that control Type 2 immunity and inflammation is currently limited. Dendritic cells (DCs) are a highly specialised type of antigen presenting cell that can potently activate T cells and coordinate immune responses. However, surprisingly little is known about how DCs are activated and function in tissues such as the lung during Type 2 inflammation.

This project will address the key question of how the lung environment modulates the ability of DCs to activate and direct Type 2 inflammation. The focus of the project will be the helminth Schistosoma mansoni, the immune response to which is strongly Type 2 biased and intimately involved in the pathology that accompanies infection. Schistosomiasis is second only to malaria in terms of the number of deaths caused annually by a parasitic disease. However, the key cellular and molecular networks that comprise immunity, inflammation and tissue repair against invading larval schistosomes are still unclear, particularly in the lung. Central to the project will be use of murine models to delineate the role of the lung environment (including surfactant and mucus) in controlling pulmonary DC activation and function in response to lung stage S. mansoni, with complementary work using allergens such as house dust mite.

This project will reveal exciting new information about the core mechanisms involved in coordination of pulmonary Type 2 inflammation by DCs, which may help future design of innovative therapies and vaccines for both helminth infection and allergies.

Training/techniques to be provided:
The successful candidate will receive training in a range of cutting-edge immunological techniques used in the MacDonald and Allen labs, including multi-parameter flow cytometry and mass cytometry (CyTOF), as well as gaining significant experience in in vivo models of inflammation, infection and allergy. Additional approaches such as refined isolation of immune cells from tissues, quantitative PCR, confocal microscopy and ELISA will also be used to define the activation and function of pulmonary DCs ex vivo and in vitro.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in Immunology or a closely related area/subject. Candidates with experience in cellular immunology or with an interest in mechanistic understanding of inflammation during helminth infection and/or allergic disease are encouraged to apply.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy 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

Freya R. Svedberg, Sheila L. Brown…, Peter C. Cook and Andrew S. MacDonald. The lung environment controls alveolar macrophage metabolism and responsiveness during type-2 inflammation. 2019. Nature Immunology. 20:571-580

Lauren M. Webb, Rachel J. Lundie, Jessica G. Borger, Sheila L. Brown, Lisa M. Connor, Adam N. R. Cartwright, Annette M. Dougall, Ruud H.P. Wilbers, Peter C. Cook, Lucy H. Jackson-Jones, Alexander T. Phythian-Adams, Cecilia Johansson, Daniel M. Davis, Benjamin G. Dewals, Franca Ronchese and Andrew S. MacDonald. A central role for Type I IFN in Th2 response induction by dendritic cells. 2017. EMBO Journal. 36:2404-2418

Rachel J. Lundie, Lauren M. Webb, Angela K. Marley, Alexander T. Phythian-Adams, Peter C. Cook, Lucy H. Jones, Sheila Brown, Rick M. Maizels, Louis Boon, Meredith O’Keefe and Andrew S. MacDonald. A central role for hepatic conventional dendritic cells in supporting Th2 responses during helminth infection. 2016. Immunology and Cell Biology. 94:400-410

Peter C. Cook, Heather Owen…, Adrian Bird and Andrew S. MacDonald. A dominant role for the methyl-CpG binding domain protein Mbd2 in controlling Th2 induction by dendritic cells. 2015. Nature Communications. 6: 6920

Carlos Minutti, Lucy Jackson-Jones…. Cristina Casals and Judith E. Allen. Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver. 2017. Science 356, pp. 1076-1080

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