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

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.

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