Immunology of Digestive Disease
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
We are working on deciphering mechanisms of sensing of microbes by the immune system and how that is perturbed in diseases such as Crohn’s disease, a major inflammatory bowel disease resulting from breakdown in the normally friendly relationship between microbes present in the bowel and immune cells present in the gut wall. We use large-scale state of the art molecular approaches in primary human cells to decipher molecular pathways that are deranged in inflammatory disease in order to highlight molecules in these pathways that may be amenable to therapeutic manipulation.
Technical Summary
Goals To define mechanisms of innate immune sensing, how defects in these processes lead to inflammation and how pathogens usurp detection by innate sensors. The HIV-1 accessory gene nef is a key HIV-1 pathogenicity factor. Our previous work showed that Nef increases the replicative capacity of HIV-1 in CD4+ T cells by triggering a signalling pathway mimicing CD4+ T cell activation with anti-CD3, and inducing key host cell factors required for viral replication (1). Proteomic analysis of CD4+ T cell signalling compartments showed that Nef positively regulates signalling by interfering with ubiquination and destruction of key CD4+ T cell signalling molecules and inhibiting Cbl activity (2). Mucosal DCs are the first cells encountered by HIV-1. They continuously sample environmental material and generate signals that determine either maintenance of immunological tolerance or activation of an adaptive immune response. Internalization of HIV-1 into DCs is mediated by dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), important in dissemination of HIV-1 infection. To investigate the suggestion that pathogens can subvert DC-SIGN functions to avoid immune recognition we studied the signalling pathway activated by DC-SIGN triggering and showed that the signalling cascade involves activation of Rho via the guanine nucleotide exchange factor (GEF) leukaemia associated Rho GEF (LARG), important for enhancing infectious synapse formation (3). LARG has since been shown to be an essential factor for HIV-1 replication. The chronic gastrointestinal illness Crohn’s disease (CD) is thought to be due to a breakdown in immune tolerance to commensal bacteria in patients with a certain genetic background. The strongest associated CD susceptibility gene is NOD2, a cytosolic recognition receptor controlling immunity against intracellular bacteria and the inflammatory response, expressed exclusively in the monocyte lineage cells, intestinal epithelial cells and Paneth cells. We have shown that NOD2 senses intracellular bacteria and links with the antigen presentation machinery in DCs, can induce autophagy in these cells in concert with another CD susceptibility gene, ATG161L1, and is necessary for bacterial handling of MHC class II antigen presentation by human DCs. DC in CD patients are autophagy induction defective and have defects in MHC class II antigen presentation and bacterial destruction. These defects could result in abnormal clearance of bacterial components and trigger mucosal inflammation. For the first time we linked two of the strongest CD susceptibility genes within a single functional pathway (4). Most recently we have found that DCs in CD patients fail to induce miR-29 in response to NOD2 stimulation, and so do not downregulate IL-23 adequately at the end of an immune response (5). Future research plans Future work will concentrate on characterizing: (a) the function of NOD2 in relation to other PRRs and its role in intestinal epithelial cells and Paneth cells; (b) the mechanism of NOD2 mediated autophagy; (c) how post-translational modifications in microbes alter PRR sensing; (d) mechanisms of nucleic acid sensing in DCs and their implication for DC function; and on (e) genomic and chemical library screening of pathways, such as xenophagy, that are dysregulated in CD to define druggable targets. References: (1) Simmons et al. 2001 Immunity 14:763 (2) Simmons et al. 2005 Immunity 23:621 (3) Hodges et al. 2007 Nature Immunol 8: 569 (4) Cooney et al. 2010 Nature Med 16: 90 (5) Brain et al. 2010 Autophagy 3: 412.
Organisations
- University of Oxford (Lead Research Organisation)
- UNIVERSITY OF OXFORD (Collaboration)
- Eberhard Karls University of Tübingen (Collaboration)
- Academic Medical Center (Collaboration)
- UNIVERSITY OF LIVERPOOL (Collaboration)
- University of Leuven (Collaboration)
- Massachusetts Institute of Technology (Collaboration)
People |
ORCID iD |
Alison Simmons (Principal Investigator) |
Publications
Serra EG
(2020)
Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.
in Nature communications
Fawkner-Corbett D
(2021)
Spatiotemporal analysis of human intestinal development at single-cell resolution.
in Cell
Tran F
(2020)
Stem Cells and Organoid Technology in Precision Medicine in Inflammation: Are We There Yet?
in Frontiers in Immunology
Kinchen J
(2018)
Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease.
in Cell
Sousa Gerós A
(2020)
The battle for iron in enteric infections.
in Immunology
Kennedy NA
(2018)
The Impact of NOD2 Variants on Fecal Microbiota in Crohn's Disease and Controls Without Gastrointestinal Disease.
in Inflammatory bowel diseases
Gibani MM
(2019)
The Impact of Vaccination and Prior Exposure on Stool Shedding of Salmonella Typhi and Salmonella Paratyphi in 6 Controlled Human Infection Studies.
in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00008/1 | 31/03/2017 | 30/03/2023 | £2,738,000 | ||
MC_UU_00008/2 | Transfer | MC_UU_00008/1 | 31/03/2017 | 30/03/2023 | £1,821,000 |
MC_UU_00008/3 | Transfer | MC_UU_00008/2 | 31/03/2017 | 30/03/2023 | £2,257,000 |
MC_UU_00008/4 | Transfer | MC_UU_00008/3 | 31/03/2017 | 30/03/2023 | £1,459,000 |
MC_UU_00008/5 | Transfer | MC_UU_00008/4 | 31/03/2017 | 30/03/2023 | £1,346,000 |
MC_UU_00008/6 | Transfer | MC_UU_00008/5 | 31/03/2017 | 30/03/2023 | £1,660,000 |
MC_UU_00008/7 | Transfer | MC_UU_00008/6 | 31/03/2017 | 30/03/2023 | £401,000 |
MC_UU_00008/8 | Transfer | MC_UU_00008/7 | 31/03/2017 | 31/03/2024 | £2,876,000 |
MC_UU_00008/9 | Transfer | MC_UU_00008/8 | 31/03/2017 | 30/03/2023 | £2,568,000 |
MC_UU_00008/10 | Transfer | MC_UU_00008/9 | 31/03/2017 | 30/03/2023 | £2,060,000 |
MC_UU_00008/11 | Transfer | MC_UU_00008/10 | 31/03/2017 | 30/03/2023 | £1,477,000 |
Description | Evotec LAB282 Partnership Award |
Amount | £249,000 (GBP) |
Funding ID | EVT08165 |
Organisation | Evotec |
Sector | Private |
Country | Germany |
Start | 02/2019 |
End | 05/2020 |
Description | HCA / MRC Definition of human intestinal mesenchymal origins and mesenchymal epithelial cross talk in intestinal development |
Amount | £107,000 (GBP) |
Funding ID | MR/SO36377/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2018 |
End | 12/2020 |
Description | Investigator Award. Defining determinantas of intestinal barrier health and disease. |
Amount | £2,097,551 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2020 |
End | 03/2025 |
Description | Lee Placito Fellowship Award (Dr Tarun Gupta) |
Amount | £311,887 (GBP) |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2018 |
End | 09/2021 |
Description | NIHR Senior Investigator Award |
Amount | £80,000 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 02/2020 |
End | 02/2024 |
Description | Oxford NIHR Biomedical Research Centre Clinical Research Career Development Fellowship |
Amount | £18,000 (GBP) |
Funding ID | David Fawkner-Corbett |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start |
Description | Oxford NIHR Biomedical Research Centre, Gastroenterology and Mucosal Immunology Theme (1 of 6 co-PIs) |
Amount | £5,000,000 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start |
Description | Programme grant: Single cell analysis of lesional pathology in IBD |
Amount | £793,146 (GBP) |
Organisation | Bristol-Myers Squibb |
Department | Celgene |
Sector | Private |
Country | United States |
Start | 05/2019 |
End | 05/2021 |
Description | RIPK2 activity in IBD |
Amount | £281,000 (GBP) |
Organisation | Bristol-Myers Squibb |
Department | Celgene |
Sector | Private |
Country | United States |
Start | 03/2017 |
End | 03/2019 |
Description | TRex Bio - Programme Grant: Building of a resource of single cell data documenting immune pathology in gastrointestinal disease, Nov 2020 - Oct 2022; £456,845.00 |
Amount | £45,684,500 (GBP) |
Funding ID | HBR03690 |
Organisation | Trex |
Sector | Private |
Country | United States |
Start | 11/2020 |
End | 10/2022 |
Description | Wellcome Trust Training Fellowship for DPhil in Biomedical and Clinical Sciences (David Fawkner-Corbett) |
Amount | £173,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2018 |
End | 10/2021 |
Description | antibody discovery initiative award: Disruption of a T cell recruitment and retention gradient for the treatment of chronic intestinal inflammation in IBD. |
Amount | £458,192 (GBP) |
Funding ID | MR/S025952/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2019 |
End | 07/2020 |
Title | STARFINDer: Spatio-Temporal Analysis Resource of Fetal Intestinal Development |
Description | Interactive analyzed data with searchable functions has been provided as an online resource - the Spatio-Temporal Analysis Resource of Fetal Intestinal Development: STAR-FINDer (https://simmonslab.shinyapps.io/FetalAtlasDataPortal/). STAR-FINDer has features including: gene expression, ST, gene regulator networks, trajectory analysis, time-course differences; morphogen expression; RL interactions. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | The development of this publicly available resource has resulted in accelerated research across the wider intestinal immunology and development research community, as it provides a widely used, highly cited and accessible resource for the research community. The resource identified and profiled using spatial and single cell technologies 101 cell states including epithelial and mesenchymal progenitor populations and programs linked to key morphogenetic milestones. The interactive data portal allows querying principles of crypt-villus axis formation; neural, vascular, mesenchymal morphogenesis, and immune population of the developing gut, as well as differentiation hierarchies of developing fibroblast and myofibroblast subtypes and describe diverse functions for these including as vascular niche cells.The online resource also contains an unbiased analysis of morphogen gradients that direct sequential waves of cellular differentiation and define cells and locations linked to rare developmental intestinal disorders. Taken together, this is a unique resource that has been of great use to the broader research community not just in the cellular biology field but also widely used for computational methods and model development. |
URL | https://simmonslab.shinyapps.io/FetalAtlasDataPortal/ |
Title | Single cell RNA-seq dataset of human and mouse colonic mesenchymal cells in health and inflammatory bowel disease |
Description | Intestinal mesenchymal cells play vital roles in epithelial homeostasis, matrix remodelling, immunity, and inflammation. But the extent of heterogeneity within the colonic mesenchyme in these processes remains unknown. Using unbiased single-cell profiling of over 16,500 colonic mesenchymal cells, this dataset reveals four subsets of fibroblasts expressing divergent transcriptional regulators and functional pathways, in addition to pericytes and myofibroblasts and how these populations are dysregulated in inflammation. |
Type Of Material | Database/Collection of data |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | This dataset generated here is the first large scale single cell profiling study of human colonic mesenchymal cells available publicly and has transformed our understanding of the diverse roles these cells play in health and disease. This work and dataset has been widely re-used by the research community and has been highly cited. |
URL | https://data.humancellatlas.org/explore/projects/f8aa201c-4ff1-45a4-890e-840d63459ca2 |
Title | Single-cell atlas of colonic CD8+ T cells in ulcerative colitis |
Description | Multimodal single-cell atlas of CD8+ cells from the human colon in health and UC, defining T-cell changes in active disease, coupled with T-cell receptor (TCR) analysis to define the functional interrelationship of identified cell states and their crosstalk with epithelial cell subtypes. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | This dataset provides a multi modal single cell and TCR profiling resource of CD8+ T cells, leading to a greater understanding of their heterogeneity and perturbations in active inflammation. This highly cited data resource is publicly available and has been used by the broader immunology research community. |
Title | scRNA-Seq Atlas of Colonic Epithelium in Health and IBD |
Description | This dataset characterises the composition of the intestinal epithelial cells in health and Ulcerative Colitis in order to identify drivers of intestinal inflammation at the molecular level. The dataset is generated from human biopsy samples taken from colonic biopsies collected from healthy patients and those with UC inflammation from an inflamed area of colon and adjacent non-inflamed area. The dataset comprises 11,175 colonic epithelial cells, capturing all epithelial cells from both absorptive and secretory lineages. |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | This dataset identified and characterised epithelial cellular subtypes, including gradients of progenitor cells, colonocytes and goblet cells within intestinal crypts. At the top of the crypts, this dataset idenfitied a previously unknown absorptive cell, expressing the proton channel OTOP2 and the satiety peptide uroguanylin, that senses pH and is dysregulated in inflammation and cancer. This dataset also enabled identification of a goblet specific antiprotease WFDC2 that inhibits bacterial growth and preserves the integrity of tight junctions but is lost in pathological intestinal inflammation. This dataset has been very widely cited and re-used by the research community in subsequent studies focused on both intestinal biology and computational methods development. |
URL | https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE116222 |
Description | Immune pathways in IBD |
Organisation | Academic Medical Center |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | Provision of technology, culture methods, cellular material and data |
Collaborator Contribution | Provision of data |
Impact | Publications in pipeline |
Start Year | 2011 |
Description | MRC Salmonella Collaboration |
Organisation | University of Liverpool |
Department | Institute of Infection and Global Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise, lab facilities, data, clinical research materials, support stafff (computational biologists, clincians), analysis. |
Collaborator Contribution | Expertise, data, support staff, analysis. |
Impact | Still active, ongoing collaboration. |
Start Year | 2014 |
Description | Mechanism of TLR8 sensing in human cells |
Organisation | Eberhard Karls University of Tübingen |
Department | Institute for Cell Biology |
Country | Germany |
Sector | Academic/University |
PI Contribution | Provided core data |
Collaborator Contribution | Provided core data |
Impact | Manuscripts in review |
Start Year | 2011 |
Description | Mechanisms of innate immune sensing |
Organisation | University of Oxford |
Department | Centre for Cellular and Molecular Physiology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Multiple proteomic experiments |
Collaborator Contribution | Provided expertise for use of proteomic facility |
Impact | Publications |
Start Year | 2006 |
Description | Stratification of Crohn's disease |
Organisation | Massachusetts Institute of Technology |
Department | Department of Biological Engineering |
Country | United States |
Sector | Academic/University |
PI Contribution | We have defined signaling paths of relevance for disease stratifcation in Crohn's |
Collaborator Contribution | Co-supervision of computational biologist in my group |
Impact | Publications and IP in pipeline |
Start Year | 2012 |
Description | eQTL mapping CD |
Organisation | University of Oxford |
Department | Wellcome Trust Centre for Human Genetics |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | Design of experiment, provision of biological samples and data |
Collaborator Contribution | Design of experiment and provision data |
Impact | Will generate publications |
Start Year | 2011 |
Description | miR-29 in IBD |
Organisation | University of Leuven |
Country | Belgium |
Sector | Academic/University |
PI Contribution | Defined role for miR-29 in NOD2 biology |
Collaborator Contribution | Collaborative experiments with miR-29 KO mouse generated in their lab |
Impact | Publication in revision |
Start Year | 2012 |
Company Name | TRexBio |
Description | TRexBio is a discovery stage company leveraging cutting edge computational biology tools, a focus on human tissue, and expertise in immunobiology to develop revolutionary therapeutics for immune-mediated diseases. Deep Biology platform maps human tissue Treg behavior to disease processes to identify and characterise novel targets for therapeutic intervention. Leveraging this platform, TRexBio is building a broad portfolio of novel therapies that modulate the immune system to restore human tissue immune homeostasis. TRexBio was founded and seed funded by SV Health Investors in 2018 and is headquartered in South San Francisco, California. |
Year Established | 2018 |
Impact | TRexBio has signed collaboration with Janssen, the latter will use TRexBio's platform to discover novel targets that aim to address unmet needs in immune-mediated disease. |
Website | https://trex.bio |
Description | Horton Patient Engagement Event |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Patients, family and carers living with IBD attended a presentation and informal discussion evening with the research team, including nurses, clinicians and research scientists. Attendees were told of opportunities to get involved in research locally and told about what is currently being worked on in the lab and the patient impact. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.oxfordgmiregistry.org.uk/events/horton-patient-engagement |
Description | Hosting a work experience visit within In2ScienceUK programme |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Secondary school student shadowed researchers at Simmons Lab for 2 weeks as part of In2ScienceUK programme. |
Year(s) Of Engagement Activity | 2019 |
URL | https://in2scienceuk.org/ |
Description | In 2 Science work experience hosting |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Work experience students from disadvantaged backgrounds spent time in the lab meeting and working with the resarch team. |
Year(s) Of Engagement Activity | 2018 |
URL | http://in2scienceuk.org/ |
Description | MRC Development Cell Atlas Kick-Off Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | A clinical research fellow from the research team attended the MRC Development Cell Atlas Kick-off meeting hosted by the Wellcome Trust, Cambridge. To forge relationships, widen knowledge and form potential collaborations with other research groups working in this field. |
Year(s) Of Engagement Activity | 2018 |
Description | MRC Festival of Research - organising a stand showcasing research on cancer immunotherapy - 23rd June 2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Researchers from Simmons Lab spent a day engaging with the public at Westgate shopping centre in Oxford explaining research on cancer immunotherapy. The stand was part of MRC Festival of Research. |
Year(s) Of Engagement Activity | 2019 |
URL | https://mrc.ukri.org/about/getting-involved/mrcfestival/ |
Description | Talk during State School Study Day in Medicine and Biomedical Sciences at St John's College 8th June 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | One of the lab members had an interactive talk about what is like to do science to 16 year old school children from disadvantaged backgrounds. This was part of school access day at St John's College on 8th June 2019. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.sjc.ox.ac.uk/discover/news/joint-medicine-and-biomedical-sciences-study-day/ |
Description | Targeting Immune Pathways - Sample Pathway, 31st January 2020 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Nurses and research practitioners attended a 'sample pathway' orientation day at the WIMM on 31st January 2020. Following introductions by Professor Simmons and some of the scientists in her lab, a comprehensive presentation of what happens to the samples collected at site on their arrival to the WIMM was given. Following questions and discussion of collection and processing issues at site to maximise the quality of samples, participants attended a tour of the technical facilities in the WIMM. |
Year(s) Of Engagement Activity | 2020 |