Innate pathways in inflammatory and infectious disease

Lead Research Organisation: University of Oxford

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.

Publications

10 25 50

 
Description Academic site reviewer in Europe eg Linkoping University Sweden 2014
Geographic Reach Asia 
Policy Influence Type Participation in advisory committee
 
Description British Society for Gastroenterology Scientific strategy committee
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Multiple clinical and academic managerial committees in Oxford and nationally (HIU, WIMM, TGU, NOCRI UK gastroenterology) Ongoing
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description National Association for Crohn's and Colitis funding committee
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Speaker at the Wellcome Genome Campus Advanced Course: Immunophenotyping
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Bill and Melinda Gates foundation co-applicant with Professor Hubbell (EPFL) (Nanoparticulate delivery vaccine adjuvants and immune priming in lymphoid tissue)
Amount £1,900,000 (GBP)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2010 
End 06/2012
 
Description Bioinformatics Project
Amount £490,000 (GBP)
Organisation Celgene 
Sector Private
Country United States
Start 02/2018 
End 01/2021
 
Description Comparative gut eukaryotic microbiome in inflammatory bowel disease
Amount £30,000 (GBP)
Organisation British Council 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2015 
End 12/2016
 
Description DNA repair and innate sensing
Amount £276,000 (GBP)
Organisation University of Oxford 
Department The Lee-Placito Medical Fund
Sector Academic/University
Country United Kingdom
Start 01/2013 
End 06/2016
 
Description Definition of New Targets for Fibrosis in Crohn's
Amount £431,000 (GBP)
Organisation Celgene 
Sector Private
Country United States
Start 04/2016 
End 09/2019
 
Description Drp1 pathway biomarker testing and stratification in Crohn's
Amount £309,000 (GBP)
Organisation AbbVie Inc 
Sector Private
Country Global
Start 01/2014 
End 06/2017
 
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 Fondation Philippe Weiner Maurice Anspach (HIV-1 infection in gut mucosal cells)
Amount £100,000 (GBP)
Organisation Wiener-Anspach Foundation 
Sector Learned Society
Country Belgium
Start 01/2010 
End 06/2011
 
Description Function of NOD2 in health and in Crohn's disease
Amount £832,000 (GBP)
Funding ID 102974/Z/13/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 06/2016
 
Description Genetics of IBD and disease stratification
Amount £1,399,000 (GBP)
Organisation Eli Lilly & Company Ltd 
Sector Private
Country United Kingdom
Start 01/2013 
End 06/2016
 
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 Academic/University
Country United Kingdom
Start 12/2018 
End 12/2020
 
Description HEFCE Senior Clinical Lecturer Award (Innate immune pathways in infectious and inflammatory disease)
Amount £500,000 (GBP)
Organisation Higher Education Funding Council for England 
Sector Public
Country United Kingdom
Start 01/2009 
End 06/2014
 
Description IOIBD (Autophagy pathways in mucosal cells in IBD)
Amount £50,000 (GBP)
Organisation International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) 
Sector Charity/Non Profit
Country Netherlands
Start 01/2010 
End 06/2011
 
Description Lee Placito Fellowship Award (Dr Tarun Gupta)
Amount £311,887 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 09/2021
 
Description MRC Human Immmunology Unit (1 of 10 co PIs)
Amount £20,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description Marie Curie fellowship (Information processing of commensal bacterial products by mucosal dendritic cells)
Amount £200,000 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 01/2010 
End 06/2012
 
Description Medical Research Awards 2017
Amount £25,000 (GBP)
Organisation Crohn's and Colitis UK 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2017 
End 04/2019
 
Description Microbes and NOD2 interaction in CD
Amount £35,000 (GBP)
Organisation Ajinomoto 
Sector Public
Country Japan
Start 01/2014 
End 06/2017
 
Description NDM studentship/Rhodes scholar (Secretory pathway function of NOD2 in intestinal mucosal cells)
Amount £180,000 (GBP)
Organisation University of Oxford 
Department Nuffield Department of Medicine
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 06/2015
 
Description NIHR Principal Investigator Salary Support
Amount £63,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start  
 
Description NIHR Research Professorship
Amount £1,800,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2013 
End 06/2018
 
Description NOD2 mitochondrial axis in innate immunity
Amount £200,000 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 01/2013 
End 06/2016
 
Description Oxford NIHR BMRC funding (Investigation of the extent to which autophagy pathways are defective in Crohn Disease)
Amount £250,000 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 01/2009 
End 06/2012
 
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 Oxford Wellcome Clinical Training fellowship (Mechanism of NOD2 and inflammasome cross-talk)
Amount £250,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2008 
End 06/2011
 
Description Oxford biomedical research centre funding (Stratification of the Oxford IBD cohort)
Amount £267,000 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 01/2012 
End 06/2014
 
Description Principal Investigator BRC Principal Fellow
Amount £45,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start  
 
Description Principal Investigator Clinical Research Network salary support
Amount £26,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start  
 
Description RIPK2 activity in IBD
Amount £281,000 (GBP)
Organisation Celgene 
Sector Private
Country United States
Start 04/2017 
End 03/2019
 
Description Serine hydorlase activity in GI inflammation
Amount £466,000 (GBP)
Organisation Abide Therapeutics 
Sector Private
Country United States
Start 01/2014 
End 06/2017
 
Description Sir Jules Thorn Award (Defining Druggable Targets in Crohn's)
Amount £750,000 (GBP)
Organisation Sir Jules Thorn Charitable Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 06/2015
 
Description Study of disease mechanisms in enteric fever to characterise innate and adaptive immunity in the mucosa and peripheral blood using controlled human infection
Amount £3,866,000 (GBP)
Funding ID MR/K021222/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2013 
End 06/2016
 
Description The Africa Oxford Initiative Travel Grant
Amount £3,000 (GBP)
Funding ID AfiOX-33 
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 08/2017 
End 07/2018
 
Description Therapeutic targeting of intestinal tissue resident T (TRM) cells in Inflammatory Bowel Disease (IBD)
Amount £250,000 (GBP)
Funding ID LAB282 37 - OUI - EVT06541 
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 06/2017 
End 12/2018
 
Description UCB post-doctoral fellowship
Amount £230,000 (GBP)
Organisation UCB Pharma 
Sector Private
Country United Kingdom
Start 01/2013 
End 06/2015
 
Description Vertex Research Grant (Identification of cellular factors involved in NOD2 mediated autophagy)
Amount £100,000 (GBP)
Organisation Vertex Pharmaceuticals 
Sector Private
Country United States
Start 01/2010 
End 06/2011
 
Description WIMM MRC studentship (Mechanisms of nucleic acid sensing and signaling in dendritic cells)
Amount £200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 06/2014
 
Description Wellcome Clinical Training Fellowship (HIV-1 escape from innate immunity in early infection and in mucosal associated lymphoid tissue)
Amount £350,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2008 
End 06/2012
 
Description Wellcome Clinical Training Fellowship (Mechanism of intracellular sensing and cross-talk between NLRs)
Amount £250,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 06/2013
 
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 10/2018 
End 10/2021
 
Description Wellcome Trust project grant (Mechanism of NOD2 mediated autophagy)
Amount £250,000 (GBP)
Funding ID 093017 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 06/2012
 
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 Tubingen
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 Nanoparticle formulations for vaccine adjuvants 
Organisation Swiss Federal Institute of Technology in Lausanne (EPFL)
Country Switzerland 
Sector Public 
PI Contribution Analysing the ability of various novel nanoparticulate formations to trigger innate immune signaling and activate the adaptive immune response in human cells
Collaborator Contribution Provision of panels of novel nanoparticle formulations
Impact Publications in pipeline
Start Year 2010
 
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 UK and International IBD Consortium 
Organisation UK and International IBD Consortium
Country Global 
Sector Academic/University 
PI Contribution Build of local IBD cohort with associated database. Identification of donors, enrolment and provision of phenotypic data and biological samples to consortia studies. Design of specific studies.
Collaborator Contribution As above.
Impact Whole genome sequence, immunochip and GWAS data for our local cohort of IBD patients. Publications resulting from this work.
Start Year 2010
 
Description eQTL mapping CD 
Organisation University of Oxford
Department Wellcome Trust Centre for Human Genetics
Country United Kingdom 
Sector Academic/University 
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
 
Title miR-29 as a Biomarker or Therapeutic in Crohn's 
Description Method to detect or treat specific form of inflammatory lesion in Crohn's 
IP Reference GB1204391.5 
Protection Patent application published
Year Protection Granted 2013
Licensed No
Impact N/A
 
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 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 Oxford University Curiosity Carnival, European Researchers' Night (29th September 2017) 
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 Various members of the group were involved in running stalls and activities to help promote and improve knowledge of what research is, what researchers do and the connections their work has to daily life, during a city wide evening of events focusing on the research taking place at Oxford University. One of the group's primary activities was the design and set up of an engagement activity called 'The Blood Factory'. Helping promote understanding into the way the body makes blood with a particular focus on immunity. Linking current research to 'everyday' science.
Year(s) Of Engagement Activity 2017
URL http://www.ox.ac.uk/curiosity-carnival
 
Description Oxfordshire Science Festival, Oxford 
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 Group members took part running stalls and activities as part of the Oxfordshire Science Festival in June 2017. A diary of events designed to promote the science taking place in Oxford.
Year(s) Of Engagement Activity 2017
URL https://www.oxscifest.com/
 
Description Patient and Public Involvement in Gastroenterology and Mucosal Immunology Research Open Evening 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact A PPI event to consult and listen to public views was held on 7th September 2016. The target audience were
patients and their family members who have been diagnosed with inflammatory bowel conditions who have
attended Endoscopy and Outpatient appointments in the Oxford University Hospitals NHS Foundation Trust.
The aim of this event was to help the public become better informed about the research that is taking place in
the trust and how they can become involved. Overall the event was designed to create a more collaborative
approach between patients and the research team.
Year(s) Of Engagement Activity 2016