BBSRC DTP Targeted Studentships - October 2019 entry

This year the BBSRC DTP Programme and Department of Pathology are offering two targeted studentships. The projects are based within the Department of Pathology, but a 10-week rotation will take place in another lab and the successful applicants will also be required to attend all DTP Programme training courses, events and a three month internship (PIPS). The successful applicants must complete the Programme in 48 months.

All applications should be made online via the University’s Applicant Portal using the Department of Pathology course code (BLPA22). Please ensure you apply via the Departmental code in the Applicant Portal (NOT the BBSRC DTP course code). An application is only complete when all supporting documents, including the 2 academic references, are submitted. It is the applicants’ responsibility to ensure their referees submit their references before the closing date.

The available projects are shown below. Applicants should hold or be about to achieve a First or Upper-Second (2.i) class degree in a relevant subject. Additionally, the Department requires that by the time of interview all potential students must have fulfilled the Language Requirements for admission. 

Supervisors and Projects available for October 2018 are:

Dr Betty Chung – The role of RNA elements that control protein synthesis during host pathogen interaction

Understanding host responses to pathogen infection is critical for guiding the development of intervention strategies. Changes in gene expression are commonly observed upon infection, as exemplified by numerous transcriptomic studies. However, techniques to analyse genome-wide responses at the level of protein synthesis have only recently become available with ribosome profiling, permitting a more sophisticated interrogation of host-pathogen interaction at the level of translation. This project will focus on the synthesis of flagellin in the food-borne enteric pathogen Salmonella enterica. Flagellin is a major virulence factor as it helps the bacterium swim to its preferred site of infection inside the host and is also a key antigen for the host innate immune system. The major structural component of flagella consists of thousands of copies of flagellin monomer protein and Salmonella undergoes phase-switching to produce two types of flagellin - FljB or FliC - allowing the pathogen to evade the host immune s system. Indeed, it was shown that FljB phase 2 flagellin is involved in the intestinal stage of infection but the bacterium switches to FliC phase 1 flagellin synthesis for systemic infection [Ikeda et al 2001 Infection and Immunity]. This alternative expression of the two flagellins is achieved by control of the fljBA operon encoding FljB and FljA, a repressor protein that controls expression of the distally located FliC through direct binding of the FliC 5'UTR, thus directly impeding FliC protein synthesis [Aldridge et al 2006 PNAS]. However, how this switch occurs in the context of infection is less clear and whether FljA regulates other mRNAs in a similar manner is unknown. The candidate will acquire tailored high-throughput next generation sequencing techniques, both experimentally and computationally to identify translationally regulated targets in response to stresses that modulate flagella synthesis (i.e. infection and different osmotic stresses), followed by a wide range of RNA-biochemistry to characterise the mechanisms utilised for this process.

The student will be supervised by Dr Betty Chung, in collaboration with Dr Gillian Fraser, both in the Division of Micribiology and Parasitology and Dr Andrew Firth in the Division of Virology.

Dr Colin Crump – Investigating the role of herpesvirus glycoprotein E in modulation of antiviral host responses and virus spread.

Herpesviruses are highly successful pathogens that cause disease in animals and humans. In particular, the alphaherpesvirus subfamily includes significant veterinary pathogens many of which are designated notifiable diseases by the Department for Environment, Food and Rural Affairs. For example, equine herpesvirus 1 (EHV-I) causes sporadic abortion storms with devastating economic impacts for the equine industry. In humans, alphaherpesvirus infections are generally benign or cause relatively mild disease but they can also cause a wide range of serious diseases, particularly in those with compromised or immature immune systems. For example, herpes simplex virus (HSV), which is normally associated with cold sores, can cause herpes simplex encephalitis (HSE) that has a mortality rate of 70% in untreated patients and as high as 19% in patients treated with antivirals, and herpes keratitis that is a leading cause of infectious blindness. Furthermore, there is evidence that infection with I-ISV influences a person's risk of Alzheimer's disease.

This PhD project will investigate the functions and host interactions of an important viral envelope protein, glycoprotein E (gE), which is conserved throughout alphaherpesviruses. This glycoprotein can form a complex with another viral glycoprotein I (gl) and is important for cell-tocell spread of infection. The gE-gl complex also has a potent immunoglobulin Fc-domain binding activity that is important for evasion of host immune responses.

We have recently conducted unbiased proteomics screens to identify host factors that interact with the gE-gl complex. This has identified cellular proteins involved in regulating intracellular transport and secretion, an antiviral restriction factor, and intriguingly mitochondrial proteins that may function in regulation of mitophagy. Mitochondria function in a range of cellular activities including regulation of innate immune responses and apoptosis, and many viruses modulate mitochondrial function, for example through targeting the process of mitophagy, a natural mechanism for the selective degradation of mitochondria by autophagy.

This project will investigate the roles of specific gE-gl interacting host factors during virus infection. Alternative proteomics-based approaches (e.g. BiolD) will be conducted to identify additional proteins that interact specifically with extracellular or cytoplasmic domains of either gE, gl or the gE-gl complex. Gene knockout and overexpressing cell lines generated by

CRISPR/Cas9 techniques or lentivirus transduction will be used in combination with wild type or gE/gl mutant viruses to establish the role of the identified host genes during virus cell-to-cell spread and antiviral responses. Cutting-edge microscopy techniques such as super-resolution microscopy (structured illumination microscopy) and three-dimensional imaging (selective plane illumination microscopy) will be used to understand mitochondrial dynamics and virus cell-to-cell spread in live cells as part of a cross-disciplinary collaboration with the Professor Kaminski's group at the Department of Chemical Engineering and Biotechnology, where these imaging systems are under continual development.

This project will primarily use I-ISV-I as the most tractable model of alphaherpesvirus biology. In addition this work will be expanded to EHV-I to study key findings on gE/gl function. We have an active collaboration with the Animal Health Trust on the development of improved EHV-I vaccines that involves mutation of gE and gl in EHV-I .

Funding will cover the student's stipend at the current Research Council rate and University Fees for 48 months, subject to eligibility*

*The studentships are available to UK nationals and EU students who meet the UK residency requirements.

Further information about eligibility for Research Council UK funding can be found on the BBSRC DTP website.

Applications from ineligible candidates will not be considered

Fixed-term: The funds for this post are available for 4 years in the first instance.

The closing date for applications 3 January 2019