Summary
Viruses can infect as cell free virus, or transmit directly from cell-to-cell. Cell-cell spread dramatically alters susceptibility to the immune system and therapeutics, yet we have very little understanding of this process. We will use molecular virology, proteomics, and cutting-edge imaging, to work out how cell-cell spread occurs, how it enables viruses to escape immunological and therapeutic control, and how therapeutics might be overcome this problem.
Project Description
Viruses can infect as cell free virus, or transmit directly from cell-to-cell. Cell-cell spread dramatically alters susceptibility to the immune system and therapeutics, yet we have very little understanding of this process. We will use molecular virology, proteomics, and cutting-edge imaging, to work out how cell-cell spread occurs, how it enables viruses to escape immunological and therapeutic control, and how therapeutics might be altered to overcome this problem.
This work will focus on Human cytomegalovirus (HCMV). HCMV is a major cause of morbidity and mortality in the immunocompromised, and the leading infectious cause of congenital malformation. It costs healthcare in the USA alone >$4 billion/year. No vaccine is licensed, and antivirals suffer from toxicity and resistance. Using unique virological systems, we have shown that in patients, a viral protein enables HCMV to spread using a cell-cell method that protects it from the immune system. This may explain why classical vaccine/therapeutic approaches have been ineffective.
This PhD will take three approaches to find ways of therapeutically targeting virus that spreads in this way. It will determine which host and viral proteins enable this mode of spread, identifying novel therapeutic targets that could prevent it from occurring in the first place. It will use cutting edge Correlative Light/Electron Microscopy to visualise how this unique mechanism of spread occurs, and what types of therapeutics (e.g. antibodies, small molecules, peptides etc) might be able to access virus spreading by this route. Finally, it will investigate whether there are immunological pathways that could be manipulated to provide enhanced control of virus spreading in this way.
As well as determining how HCMV cell-cell spread might be controlled in vivo, this will provide a high level of training in cutting-edge virology, cell biology, molecular biology, imaging, and proteomics.
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