About the Project
The host immune system is critical in maintaining healthy interactions with “beneficial” commensal bacteria that reside in the intestinal tract. The majority of bacterial species in the gut are physically segregated from the intestinal epithelial layer, and the underlying immune system, by a thick layer of mucus, which prevents inappropriate stimulation of immune cells that could cause inflammation and tissue-damage. Nonetheless, some species of bacteria have evolved mechanisms to penetrate the mucus layer and reside in intimate contact with the host. Emerging evidence suggest these mucus-dwelling species are “pathobionts” – bacteria that are normally controlled by specific immune cell responses in the healthy intestine, but which can take advantage of changes in the environment caused by infection or disease to drive inflammation and pathology. Indeed, it is now increasingly understood that dysregulated interactions between the host immune system and intestinal-dwelling bacteria is of clinical importance in a wide range of human diseases such as Inflammatory Bowel Disease (IBD), as well as systemic inflammatory diseases such as arthritis, liver disease and more. The aim of this project is to determine how mucus-dwelling bacteria are normally controlled by the immune system in health and how they contribute to inflammation and disease when normal responses are disrupted.
The successful candidate will use cutting edge tools to dissect interactions between mucus-dwelling pathobiont bacteria with the immune system and investigate how these bacteria take advantage of changes in the local environment following infection or disease (e.g. colitis/IBD) to drive inflammation and tissue pathology.
This project will provide a unique multidisciplinary training opportunity in immunology, mucus biology and microbiology, and utilize models of infection and disease, to investigate i) how intestinal mucus-dwelling bacterial species are normally controlled by the immune system ii) how these bacteria contribute to inflammation in situations where intestinal homeostasis is lost (infection, inflammatory disease) iii) how these bacteria are adapted to live within intestinal mucus layers.
http://www.mig.manchester.ac.uk/people/richardgrencis/
http://www.mig.manchester.ac.uk/people/matthewhepworth/
http://www.mig.manchester.ac.uk/people/davethornton/
References
Chronic Trichuris muris infection in C57BL/6 mice causes significant changes in host microbiota and metabolome: Effects reversed by pathogen clearance.
Houlden A, Hayes KS, Bancroft AJ, Worthington JJ, Wang P, Grencis RK, Roberts IS
PLoS One, 2015
Immune-driven alterations in mucin suphation is an important mediator of Trichuris muris helminth expulsion
Hasnain SZ, Dawson PA, Lourie R, Hutson P, Tong H, Grencis RK, McGuckin MA, Thornton DJ.
PLoS Pathogens, 2017
Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells.
Hepworth MR, Fung TC, Masur SH, Kelsen JR, McConnell FM, Dubrot J, Withers DR, Hugues S, Farrar MA, Reith W, Eberl G, Baldassano RN, Laufer TN, Elson CO, Sonnenberg GF.
Science, 2015
New role of Nod proteins in regulation of intestinal goblet cell response in the context of innate host defense in an enteric parasite infection.
Wang H, Kim JJ, Denou E, Gallagher A, Thornton DJ, Shajib MS, Xia L, Schertzer JD, Grencis RK, Philpott DJ, Khan WI.
Infection and Immunity, 2015
Lymphoid-tissue-resident commensal bacteria promote members of the IL-10 cytokine family to establish mutualism.
Fung TC, Bessman NJ, Hepworth MR, Kumar N, Shibata N, Kobuley D, Wang K, Ziegler CG, Goc J, Shima T, Umesaki Y, Sartor RB, Sullivan KV, Lawley TD, Kunisawa J, Kiyono H, Sonnenberg GF.
Immunity, 2016
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