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.
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