Dissecting the role of RNA structure and non-canonical eIF3 dependent translation initiation in Dengue virus innate immune escape

The principal supervisors are Dr Lindsay Broadbent (Surrey), Professor Nicolas Locker (Surrey/Pribright) and Dr Trevor Sweeney (Pirbright). 

Our aim is to understand a new mechanism evolved by mosquito-borne viruses coupling protein synthesis and escape from host immunity. During infection, host cells can initiate stress responses to shut down their translation machinery which viruses rely on for their own protein synthesis. In consequence, viruses have engineered alternative translation pathways to commandeer the host machinery and produce viral proteins. Together, Professor Locker at the University of Surrey and Dr Sweeney at the Pirbright Institute previously uncovered a new mechanism of protein synthesis by dengue virus (DENV) where the cellular translation factor eIF3 is hijacked by the DENV RNA to mediate viral translation. They now have evidence that this impacts on antiviral responses by counteracting the detection of viral RNAs by the host sensor protein IFIT1, and thus induction of antiviral responses which Dr Lindsay Broadbent has long standing expertise in. Therefore this multi-disciplinary project bridges the gap between RNA biology, antiviral immunity and translational control.   

Funded by a Doctoral Training Partnership between the University of Surrey and the Pirbright Institute, the objectives of this PhD project are to characterize the mechanisms by which eIF3 interaction with DENV RNA allows escape from innate immunity, which will inform novel therapeutic avenues for diseases of clinical and economical importance.  

Using a combination of cell-based assays (CRISPR-based silencing, viral replication assays) and molecular virology approaches (RNA structure, ELISA, binding assays, IFN signalling, microscopy) the specific aims are to:

1. Determine impact of eIF3 binding to DENV RNA on IFIT dependent translation control.
2. Determine impact of mutations that disrupt eIF3 binding on DENV translation and replication.
3. Examine if mutations that disrupt eIF3 binding affect the host interferon response.

Open to UK student with the project starting in October 2023.

You will need to meet the minimum entry requirements for our PhD programme https://www.surrey.ac.uk/postgraduate/biosciences-and-medicine-phd#entry.