Investigating the modulation of immunity to persistent viral infection by the death receptor 3/TNF-like 1A pathway

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

Abstract

Death Receptor 3 (DR3) is a recently discovered protein that has been shown to control inflammation, the process by which the body responds to injury or irritation by pain, swelling, redness and heat. Normally, inflammation is short-lived and the body recovers quickly, but in certain diseases, inflammation becomes chronic resulting in much longer-term discomfort and can become life-threatening when it affects an essential organ. Inflammatory diseases affect up to 10% of the population at some point in their lives. Recently, DR3 has been suggested as a potential target for new therapies against multiple inflammatory diseases ranging from rheumatoid arthritis to inflammatory bowel disease. This project is designed to increase our understanding of how DR3 controls other aspects of our immune response, namely those to viruses. This is essential as it may reveal potential side-effects that could be associated with therapies targeted against the DR3/TL1A pathway. In addition, the study is designed to reveal other important functions of DR3, which could then be used to manipulate immune responses to our own advantage. In particular, we hope to explore the potential of boosting immunity through activation of the DR3/TL1A pathway, therefore potentially aiding therapies such as vaccines against viruses and cancer.

Technical Summary

The primary aim of this project is to characterise the contribution of death receptor 3 (DR3) and its only confirmed ligand TNF-like protein 1A (TL1A) to immunity to persistent viruses. This is vitally important as DR3 is emerging as a major regulator of inflammation and anti-TL1A agents have been suggested as a potential therapeutic in a number of inflammatory diseases. Our preliminary data suggests that immunity to the persistent murine cytomegalovirus (MCMV) is impaired in DR3ko mice, which exhibit severe impairment in splenocyte expansion after MCMV challenge and an increase in MCMV titres in the salivary gland 30 days after infection, a readout that represents the establishment of persistent viral infection. Our data indicates that there are both T and non-T cell aspects of immunity to MCMV that are impaired in DR3ko mice. This proposal is designed to further explore the role of DR3 in persistent viral infection using MCMV as a model, in particular investigating whether there is an essential requirement for DR3 in immunity at early and late stages of infection, and to test whether TL1A may be used as an immunotherapeutic tool designed to boost anti-viral T cell responses. The current application has 3 main aims:
I. Characterization of DR3-dependent responses at early stages of MCMV infection
II. Analysis of DR3-dependent T cell responses in persistent MCMV infection
III. Testing of TL1A as a potential therapeutic boost for anti-viral T cell responses

Publications


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Calder CJ (2012) An essential role for death receptor 3 in experimental autoimmune uveoretinitis. in Ocular immunology and inflammation
Jia LG (2016) A Novel Role for TL1A/DR3 in Protection against Intestinal Injury and Infection. in Journal of immunology (Baltimore, Md. : 1950)
 
Description ARUK Equipment Grant
Amount £65,558 (GBP)
Organisation Arthritis Research UK 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 06/2012 
End 12/2012
 
Description BBSRC GSK CASE Studentship (top-up)
Amount £5,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2012 
End 03/2013
 
Description Commercial Supply
Amount £8,252 (GBP)
Organisation Cancer Research UK (CRUK) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2015 
End 04/2016
 
Description Commercial Supply
Amount £4,739 (GBP)
Organisation Cancer Research UK (CRUK) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2013 
End 12/2013
 
Description ISSF Seedcorn Grant
Amount £35,821 (GBP)
Funding ID AC1120IF05 
Organisation The Wellcome Trust Ltd 
Department Wellcome Trust Institutional Strategic Support Fund
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 05/2016 
End 12/2016
 
Description MRC Centenary Award
Amount £16,209 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2012 
End 03/2013
 
Description PhD Studentship
Amount £80,000 (GBP)
Organisation MRC/AZ 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2014 
End 10/2017
 
Title DR3ko DBA/1 background 
Description DR3ko mice generated by backcrosses onto a DBA/1 background 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact DR3ko DBA/1 mice are lethally susceptible to MCMV infection at low doses. They have also been used to investigate models of collagen-induced arthritis and ankylosing spondylitis. 
 
Description Atherosclerosis 
Organisation Cardiff University
Department Cardiff School of Biosciences
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Expertise and experiments
Collaborator Contribution Expertise and experiments
Impact Publication PMID: 20410491
Start Year 2009
 
Description Inflammation 
Organisation Cardiff University School of Medicine
Department Institute of Infection and Immunity
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Expertise, ideas, some research
Collaborator Contribution Expertise, reagents, experiments
Impact Publication PMID: 20826539, PhD studentship funding
Start Year 2008
 
Description MCMV 
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 Staff, reagents, intellectual input
Collaborator Contribution Intellectual input and reagents
Impact Successful grant funding - MRC Project Grant awarded in 2009
Start Year 2007
 
Description Neurology A 
Organisation Cardiff University
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Experiments, expertise
Collaborator Contribution Expertise
Impact Publication PMID: 20220013
Start Year 2007
 
Description Neurology B 
Organisation University of Barcelona (UB)
Country Spain, Kingdom of 
Sector Academic/University 
PI Contribution Experiments, expertise
Impact Publication PMID: 20220013
Start Year 2007
 
Description Neurology C 
Organisation School of Biological Sciences Cambridge
Department Department of Pathology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Experiments, expertise
Impact Publication PMID: 20220013
Start Year 2007