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Studying how the intestinal immune system functions to enable the symbiotic relationship with the intestinal microflora required for health, and how that relationship breaks down leading to inflammatory bowel disease.

None © Martin Phelps

About the research

We study how the intestinal immune system functions to enable the symbiotic relationship with the intestinal microflora required for health. We are interested in how that relationship breaks down leading to inflammatory bowel disease.

Inflammatory bowel disease affects 1 in 250 people and has been difficult to treat in some patients as little is known of the cellular make up of tissue lesions observed in different manifestations of this disease. We have used single cell technologies to create an unbiased map of single mucosal cell types present in the human or murine intestine. Applying this approach to epithelial cells enabled us to define trajectories of secretory or absorptive cells that undergo extensive remodelling in inflammatory bowel disease (IBD). A similar analysis of mesenchymal cells allowed us to define several new cell states including the colonic crypt niche cell that directs epithelial stem cell function in health. Pathological remodelling of the mesenchyme in IBD revealed pathways driving immune infiltration and impairing epithelial reconstitution in this disease (1). In current work, we are using a similar unbiased approach to define how immune cells remodel and interact with both intestinal epithelia and mesenchyme in differing forms of IBD. We will study the effect of IBD susceptibility genes (2, 3) on these processes. Dominant pathological features of IBD associated immune infiltrates are being interrogated using genetic models in vitro and in vivo. In tandem, we examine what molecular features of the enteric microflora might contribute to breakdown of immunoregulation in IBD, building on our experience documenting enteric host pathogen interactions (4, 5).

Projects available include:

1) Definition of intestinal mesenchymal cell development and characterisation of progenitor cell function in health and IBD.

2) Characterisation of pathways of colonic epithelial barrier breakdown mediated by novel epithelial cell states revealed by single-cell RNA-sequence data.

3) Characterisation of intestinal epithelial stem cell function in health and inflammation.

4) Mechanisms of immune reactivity to the intestinal microflora in IBD.

 

Training Opportunities

Students will based in the MRC Human Immunology Unit (HIU), MRC Weatherall Institute of Molecular Medicine (WIMM), a world-renowned research centre focused on defining mechanisms of disease. Students will have access to state of the art facilities and training in a broad range of techniques. Projects involve use of single-cell RNA-sequencing, single-cell ATAC-sequencing, FACS, CyTOF, confocal microscopy, CRISPR/Cas9 genetic manipulation, super-resolution microscopy, proteomic and metabolomic analysis. Some work involves use of advanced cell culture techniques including or populations of rare intestinal mucosal cells. Microbiological skills such as bacterial culture, gene targeting and sequencing may be employed. Training in computational biology and analysis of single-cell or microbial datasets will be provided as required. Our work is supported by collaborations with many scientists locally and internationally.

 

Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

 

Publications

Kinchen J, Chen HH, Parikh K, Antanaviciute A, Jagielowicz M, Fawkner-Corbett D, Ashley N, Cubitt L, Mellado-Gomez E, Attar M, Sharma E, Wills Q, Bowden R, Richter FC, Ahern D, Puri KD, Henault J, Gervais F, Koohy H, Simmons A. (2018). Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease. Cell. 2018 Oct 4;175(2):372-386.e17. PMID: 30270042

Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJ, Campbell BJ, Jewell D, Simmons A (2010). NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Medicine Jan;16(1):90-7. PMID: 19966812

Brain O, Owens BM, Pichulik T, Allan P, Khatamzas E, Leslie A, Steevels T, Sharma S, Mayer A, Catuneanu A M, Morton V, Sun M Y, Jewell D, Coccia M, Harrison O, Maloy K, Schönefeldt S, Bornschein S, Liston A, Simmons A. (2013).  The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release. Immunity Sep 19;39(3):521-36. PMID:  24054330.

Aulicino A, Rue-Albrecht KC, Preciado-Llanes L, Napolitani G, Ashley N, Cribbs A, Koth J, Lagerholm CB, Ambrose T, Gordon MA, Sims D and Simmons A. Invasive Salmonella Exploits Divergent Immune Evasion Strategies in Infected and Bystander Dendritic Cell Subsets. Accepted, Nature Communications, 2018.

Khatamzas E, Hipp MM, Gaughan D, Pichulik T, Leslie A, Fernandes RA, Muraro D, Booth S, Zausmer K, Sun MY, Kessler B, Rowland-Jones S, Cerundolo V, Simmons A. (2017). Snapin promotes HIV-1 transmission from dendritic cells by dampening TLR8 signaling. EMBO J. 36(20):2998-3011. PMID: 28923824

Supervisors