VIRAL IMMUNE EVASION · Using viral inhibitors to characterise signalling pathways involved in interferon induction
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-11-01 → 2007-10-31
- EU contribution
- €154,446
- Participants
- 1
- Scheme
- SCF
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Results in brief
Final Activity Report Summary - VIRAL IMMUNE EVASION (Using viral inhibitors to characterise signalling pathways involved in interferon induction)
The innate immune system provides an immediate response to infections, when a cell is exposed to pathogen-associated molecular patterns (PAMPS), such as viral or bacterial DNA, RNA or proteins. The innate immune response to viruses involves the production of interferon-beta, which is secreted from infected cells with the aim of establishing an 'antiviral state' within the cell, and of alerting neighbouring cells to the danger. Viruses, in turn, having co-evolved with their host, possess means to evade and inhibit the interferon response, which allows them to establish a productive infection. Vaccinia virus, a poxvirus with more than 200 genes, has a particularly large repertoire of tools to inhibit the host immune system. With the aim of finding new vaccinia virus proteins that inhibit the innate immune system, we screened 49 previously uncharacterised vaccinia virus proteins for inhibition of the interferon response in cultured human cells. Five of the 49 proteins tested had a strong inhibitory effect, blocking the expression of an interferon-beta reporter gene when the cells were exposed to cytoplasmic double-stranded RNA or DNA, which are hallmarks of viral infection. We have characterised these viral proteins in more detail, and have identified which cellular signalling pathways they inhibit. We are currently searching for host proteins that are targeted by the inhibitors. In this way, the vaccinia virus proteins that we identified may help us to understand the workings of the innate immune system. Also, the viral inhibitors could be useful for the design of therapeutics aimed at blocking excessive inflammation, for instance in arthritis and septic shock.
Data: CORDIS, © European Union
Project objective
The innate immune system is the first line of defence against invading pathogens. The immediate response against viruses involves the secretion of interferon-alpha and -beta, which induce an `anti-viral state and apos; in the infected cell and warn neighbo uring cells of the danger. Double-stranded RNA (dsRNA), a hallmark of viral infection, is a potent stimulus of the interferon response, but the molecular mechanisms involved in dsRNA recognition and subsequent signal transduction have only partially been c haracterised. We aim to identify novel components of the signalling pathways involved in interferon induction, by exploiting the fact that many viruses are able to interfere with signalling pathways that regulate the innate immune response. Large DNA virus es possess a particularly ample repertoire of immuno-modulatory genes. We will screen the genome of vaccinia virus for inhibitors of the interferon response, and identify host proteins that interact with the viral inhibitors. The cellular targets of viral inhibition are likely to be key regulators of the anti-viral response, and we will attempt to characterise their function with respect to known signalling pathways. This project, while aimed at elucidating basic cellular signalling mechanisms, may yield re sults of great medical importance. A more detailed understanding of virus-host interactions is crucial at a time when (re-)emerging infectious diseases and the potential threat of biological warfare pose new scientific challenges. Also, the study of immuno -modulatory proteins may result in the identification of novel therapeutic targets for the treatment of chronic and acute inflammatory diseases. The proposed project would allow the candidate to enter a new field of study at the interface of molecular cell biology, immunology and virology. Due to the acquisition of new technical and transferable skills, the research training would be a crucial stepping stone in the candidate and apos;s academic career path.
Original text from CORDIS.
Participants
- THE PROVOST, FELLOWS AND SCHOLARS OF THE COLLEGE OF THE HOLY AND UNDIVIDED TRINITY OF QUEEN ELIZABETH, NEAR DUBLIN (HEREINAFTER CALLED TCD) · DUBLINCoordinatorCity levelIreland
Links
Data: CORDIS, © European Union