Pattern recognition receptors and the recruitment and differentiation of myeloid cells in inflammation.

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

The main aims of the research are to understand how the immune receptor dectin-1 controls the inflammatory response after fungal infection and to develop new experimental mouse models to facilitate these and related studies of inflammation.

At the time of an infection, the body initiates an inflammatory response, the aim of which is to recruit specialised immune cells to the site of infection and contain the infectious organism. The cells express receptors on their surface that are able to recognise distinct components of microorganisms. The collective recognition of multiple microbial components by many cell surface receptors enables the immune cells to ‘identify‘ the infecting organism and promote the development of an appropriate immune response.

Dectin-1 is a key receptor involved in the recognition of fungi that binds to fungal specific carbohydrates (beta-glucans). We have shown that this receptor is essential for a normal inflammatory response after fungal infection of mice and that its absence results in increased susceptibility to infection.

Fungal infections are important because of their increasing frequency as a consequence of modern medicine and acquired defects in the immune system. These studies will help us understand how a normal protective immune response to fungal infection occurs.

Technical Summary

The primary aims of this research are: i) to determine the importance of the leukocyte beta-glucan receptor, Dectin-1, in the regulation of myeloid cell recruitment, activation, differentiation and survival during fungal infection; and ii) to develop novel models for the study of myeloid cells during inflammation.
Our initial characterisation of the leukocyte ?-glucan receptor, Dectin-1, has shown that it is broadly expressed on myeloid cells and plays a fundamental and non-redundant role in the recognition and response to fungi. Deficiency in Dectin-1 results in susceptibility to Candida albicans infection and this is associated with defective inflammatory responses. The increasing prevalence of fungal infections associated with acquired immunodeficiency and medically induced immunosuppression and the importance of Dectin-1 in anti-fungal defence have highlighted Dectin-1 as a potential therapeutic target.
It is important to understand how Dectin-1 regulates the anti-fungal inflammatory response to appreciate novel ways of manipulating the cellular response during inflammation. To achieve the aims of this proposal we will also develop models for the study of myeloid cell biology during inflammatory responses. These models will be important, not only for the study of the role of Dectin-1 in inflammation but also as a basis for improving the study of myeloid cells in models of human disease.

Publications

10 25 50
 
Description Cardiff University LREF
Amount £150,000 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2011 
End 03/2016
 
Description Cardiff University PhD Studentship
Amount £75,000 (GBP)
Organisation Cardiff University 
Department School of Medicine
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2013 
End 09/2016
 
Description Cardiff University School of Medicine awarded PhD studentship (part MRC DTG)
Amount £65,000 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2007 
End 09/2010
 
Description Cardiff University School of Medicine awarded PhD studentship (part MRC DTG)
Amount £65,000 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2010 
End 09/2013
 
Description Cardiff University School of Medicine awarded PhD studentship (part MRC DTG)
Amount £65,000 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2010 
End 09/2013
 
Description Cardiff University/MRC DTG PhD studentship
Amount £68,000 (GBP)
Organisation Cardiff University 
Department School of Medicine
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2013 
End 09/2016
 
Description MRC DTP Studentship
Amount £75,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2015 
End 03/2019
 
Description MRC Project Grant
Amount £451,852 (GBP)
Funding ID MR/K02003X/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 08/2013 
End 07/2016
 
Description MRC Project Grant
Amount £462,539 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 08/2012 
End 07/2015
 
Description Marie Curie International Fellowship
Amount £170,000 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 08/2011 
End 07/2013
 
Description Pfizer Anti-Infectives Research Foundation
Amount £32,138 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2012 
End 12/2012
 
Description Pfizer Anti-Infectives Research Foundation
Amount £48,355 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2012 
End 12/2012
 
Description Ser Cymru Capital Equipment Award
Amount £225,000 (GBP)
Organisation Health and Care Research Wales 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 03/2016 
End 02/2021
 
Description Wellcome Investigator Award
Amount £1,414,000 (GBP)
Funding ID 107964/Z/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 02/2016 
End 01/2021
 
Description Wellcome Trust Programme Grant
Amount £1,202,625 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2011 
End 03/2016
 
Description Wellcome VIP Award
Amount £23,062 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 11/2011 
End 10/2012
 
Title Inflmac 
Description Microarray dataset 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact Too soon, but included in PMID24762537 
 
Description AA 
Organisation National Jewish Medical and Research Center, USA
Country United States of America 
Sector Hospitals 
PI Contribution We have provided unique reagents and intellectual advice (some planning and interpretation)
Collaborator Contribution The collaboration has provided some novel insights to be compared with our work.
Impact 19502385
 
Description CPS 
Organisation University of Oxford
Department Jenner Institute
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We provided specialist knoweldged and performed specific experiments.
Collaborator Contribution Our collaborators have performed specialist experiments for us resulting in the generation of key new reagents that have influenced future work.
Impact 19660585
 
Description CR3 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution specialist skills and technologies and intellectual input
Collaborator Contribution led the project and conducted the majority of the experiments
Impact 23451151
Start Year 2012
 
Description Chemo 
Organisation University Paris Sud
Country France, French Republic 
Sector Academic/University 
PI Contribution Provision of specific scientific reagents and intellectual input
Collaborator Contribution led the project and conducted the experiments
Impact 23562161
Start Year 2012
 
Description D1 
Organisation University of Aberdeen
Department Institute of Medical Sciences
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Primarily intellectual input into planning and interpretation. Also some of the specialist experimental work was performed by us.
Collaborator Contribution This has been an extensive collaboration with cross-over of intellectual ideas and reagents as required.
Impact 18350551 19581397 18200499
 
Description D1Fc 
Organisation University of Lubeck
Department Institute for Inflammation Research
Country Germany, Federal Republic of 
Sector Academic/University 
PI Contribution Intellectual constributions, specific and unique reagent contribtuion, contribution to experimental design and execution.
Collaborator Contribution In this project they led. They provided
Impact PMID: 22922409
Start Year 2010
 
Description D1MR 
Organisation University of Nottingham
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We provided expertise and unique reagents to support research in another insititute
Collaborator Contribution Provided insights into cell biology questions related to our research
Impact 21205820
Start Year 2009
 
Description D2 DC 
Organisation Cancer Research UK
Department Cancer Research UK London Research Institute (LRI)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution We provided intellectual input (planning and interpretaion). We also perfomed experiments and generated unique reagents to make the project possible.
Collaborator Contribution This was a close collaboration of mixed intellectual cross-over and fully collaborative approach to experiments performed by both reseach teams.
Impact 19703985
Start Year 2008
 
Description Flu 
Organisation Cardiff University
Department Infection and Immunity
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We provided experetise and experimental support to another research team
Collaborator Contribution A collaborative research project investigating the impact of treatment on immunity
Impact 21310755 23857287
Start Year 2009
 
Description G6 
Organisation Cardiff University
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We led this research and conducted the majority of the work.
Collaborator Contribution Provided some advice and advanced analytical assistance
Impact PMID: 24762537
Start Year 2007
 
Description G6 
Organisation Cardiff University
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We led this research and conducted the majority of the work.
Collaborator Contribution Provided some advice and advanced analytical assistance
Impact PMID: 24762537
Start Year 2007
 
Description H8 
Organisation Cancer Research UK
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution We led collaboration and performed most of the investigation and initial intellectual property.
Collaborator Contribution They provided expert advice, access to reagents and experimental support.
Impact 21268006
Start Year 2009
 
Description H8n 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We led the research but benefited greatly from outside experience and experimental support
Collaborator Contribution Our collaborators provided reagents and experimental support towards the completion of the project.
Impact 21368104
Start Year 2009
 
Description H8n2 
Organisation University of Lubeck
Department Institute for Inflammation Research
Country Germany, Federal Republic of 
Sector Academic/University 
PI Contribution specialist skills, intellectual input, conducting experiment and providing unique reagents
Collaborator Contribution Leading the collaboration and co-ordinating several teams
Impact 22922409
Start Year 2010
 
Description Infl 
Organisation Cardiff University
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Intellectual input, experimental support provision of analysis macros
Collaborator Contribution They led on this project
Impact PMID: 25175678
Start Year 2012
 
Description LAB 
Organisation National Institutes of Health (NIH)
Country United States of America 
Sector Public 
PI Contribution specialist reagents and intellectual input, conducting specific experiments and provision of significant staff time.
Collaborator Contribution led the project and co-ordinated teams.
Impact 23675302
Start Year 2009
 
Description Network 
Organisation University Hospital of Wales
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution We provide expertise in cell biology to a network of researchers.
Collaborator Contribution Provided easier access to a network of expertise and potentially reagents
Impact The network is composed of 48 co-applicants and is funded to provide infrastructure for the development and funding of related research
Start Year 2009
 
Description OncM 
Organisation University Hospital of Wales
Department Department of Medical Biochemistry and Immunology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution Intellectual input: planning and inerpretation of inflammatory mechanisms.
Collaborator Contribution Intellectual input into the study of inflammation.
Impact 18641356
 
Description Prol 
Organisation Cardiff University
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We led the research and established new technologies appropriate to the novel investigations
Collaborator Contribution Provision of intellectual advice
Impact 21710478 21952806 23695680 24048120
Start Year 2010
 
Description Schisto 
Organisation Trinity College Dublin
Country Ireland, Republic of 
Sector Academic/University 
PI Contribution Provision of intellectual input and performed experiments with our unique reagents.
Impact 18981244
 
Description fib 
Organisation Cardiff University
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Intellectual input, experimental support, some experiments and data.,
Collaborator Contribution They led this research.
Impact PMID: 24412616
Start Year 2009
 
Description glucans 
Organisation East Tennessee State University
Department James H Quillen College of Medicine
Country United States of America 
Sector Academic/University 
PI Contribution The project was intellectually led by us and all experiments were performed by us with the aid of a key collaborator provided reagent.
Collaborator Contribution It has provided a unique well characterised reagent that assisted the study and could be used to validate other reagents.
Impact 18714028
Start Year 2007
 
Description lipoxygenase 
Organisation University Hospital of Wales
Department Department of Medical Biochemistry and Immunology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution We have provided intellectual expertise on myeloid cell biology and inflammator processes and we have also performed specialist experiments.
Collaborator Contribution Intellectual contribution to understanding o lipid mediators of inflammation.
Impact 18941242 19531470
 
Description Annual newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/parliamentarians
Results and Impact I compiled the 2009-12 Annual newsletters for immunology research in Cardiff, which serves as a focus for researchers in the field and for external parties interested in the output or activities of Cardiff Immunologists.

The newsletter is distributed to key policy makers in the Welsh government including the CMO and head of NISCHR.
Year(s) Of Engagement Activity 2009,2010,2011,2012
 
Description Online news 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Supply of notable scientific and otherwise (e.g. human interest) news stories from Cardiff Immunologists to a regularly updated immunology website.

This activity helps create the internet face of cardiff immunologists withan ima to increasing profile and aiding in recruitment.
Year(s) Of Engagement Activity 2009,2010,2011,2012
 
Description Open days - school visitors 
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 The School of Medicine host a Science day, which in 2009 was considered in the top 3 of such events. This involves talks and demonstrations to ~500 A levels students. I have now taken part in this scheme, primarily in 2009 in a publicity capacity ensuring external coverage (including coverage by the British Society of Immunology). This has continues on an annual basis

This event creates a deal of publicity for medical research in Cardiff and serves as a stimulus for the recruitment of future researchers and doctors.
Year(s) Of Engagement Activity 2009,2010,2011,2013