A systems approach to elucidation of protein lipidation during virus infection

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Viruses are small infectious agents and are obligate parasites in that they replicate only inside host cells. To cause disease, they must enter specific target cells, overcome barriers to infection and engage with the appropriate cellular machinery which they redirect to make more copies of themselves. This application concerns one of a major group of human viruses, the herpesviruses. These viruses cause diseases ranging from moderate but with high frequency in the population, such as cold sores, chicken pox or glandular fever, through to diseases that while less frequent, can be extremely severe and life threatening, including eye infections, diseases in newborn infants, as well as peripheral and central nervous system diseases. They are particularly dangerous in immunosuppressed patients such as transplant recipients and in AIDS patients. While we have some effective drugs, there are significant limitations with their use and they are effective only against a subset of the herpesviruses. To identify new therapeutic opportunities we must have a thorough understanding of the mechanisms of replication. Such understanding may lead to a rationale way to design novel antiviral agents which may be more broadly effective. Host cell proteins and viral proteins are modified after (or during) their synthesis with a series of different types of molecules. This process is generally termed post-translational modification and it plays a fundamental role in changing the structure, localisation, stability and function of the potential target proteins. Therefore in terms of virus infection, protein modification can be on host cell proteins and affect their ability to support virus growth or to respond to infection and mount an antiviral attack. Host protein modification can in principle remain unaffected, or specific species can be induced by the host, or by the virus, while other species may be down-regulated. Likewise modification of virus proteins can affect their function, or recruitment into assembly particles, their transport within and out of a cell or their ability to overcome host responses. One general type of such modification is called lipidation, wherein proteins are covalently coupled to any of a series of lipids (fat like molecules). This represents a key regulatory mechanism in altering proteins and thus regulating processes including membrane targeting, intracellular protein and organelle transport, signalling networks relaying communication from outside to inside the cell, cell structure, metabolic pathways, neurotransmission and immune responses. As such protein lipidation plays a profound role in normal biological functioning and disease progression. There are four broad types of lipid modification and they can take place on proteins in different combinations, altering the location and function of proteins. However lipidation is broadly less understood than other sorts of protein modification and our knowledge of the range of host and viral proteins which are modified is incomplete. This is because the most frequently utilised approaches lack sensitivity, can be slow to yield results and are not readily amenable to high-throughput analysis exploiting advances in genetic and protein bioinformatics. We aim to develop novel chemical technologies combined with high-throughput approaches on the role of lipidation of virus and host proteins in herpesvirus infection. Not only will this work yield novel insight into the identity and role of lipidation in this context, it will produce new probes and methodologies available for other systems. It will hugely accelerate our understanding of infection and our ability to perform similar studies in other disease systems not only in infectious diseases. It will enable high-throughput screening of potential new classes of therapeutics and it will provide a roadmap for multidisciplinary working bringing together chemistry and biology to yield novel insight into disease processes.