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Identification Of Druggable Targets In Pathways Common To Skin-replicating Viruses To Enable Future

Identification Of Druggable Targets In Pathways Common To Skin-replicating Viruses To Enable Future Development Of Broad-spectrum Antivirals

A 3-year PhD Studentship in the III funded by the Rosetrees Trust is available within the UCL GOS Institute of Child Health (London, UK). The studentship is expected to start in April/May 2024, under the supervision of Professor Judy Breuer and Dr Cristina Tommasi.

Project title: Identification Of Druggable Targets In Pathways Common To Skin-replicating Viruses To Enable Future Development Of Broad-spectrum Antivirals

Hypothesis/Aims:

Our group is interested in viruses that are able to replicate in skin, including monkeypox (mpox), which has recently emerged as a major public health threat, herpes simplex virus (HSV) and varicella-zoster virus (VZV), which can cause severe disseminated infections, and human papillomavirus, the cause of cervical cancer. In all cases replication in skin is critical to viral transmission and pathogenesis and the development of drugs and vaccines that interrupt viral replication in skin would have major benefits for their control.  

Preliminary data suggest that, although from different viral families, these viruses replicate using the same proteins and signalling pathways, including some that are unique to skin and indeed, this may be what confers epithelial tissue tropism. This project proposes to characterise in detail how herpes simplex and poxvirus (vaccinia and monkeypox) utilise common pathways to replicate in skin, identifying potential targets for the development of broad-spectrum antiviral therapies. 

To this aim, we will:

  1. Characterise the transcriptome and proteome of HSV-1 and vaccinia virus (VACV) in epithelial differentiation models.
  2. Characterise epidermal pathways that are critical for HSV-1 and VACV epidermal replication.
  3. Identify inhibitors of the identified pathways and therefore of HSV-1, VACV and mpox epidermal replication.

6-12 Month Plan (e.g., experimental approaches, data collection, preliminary analyses):

- training on different skin models

- training on HSV-1 and VACV viruses culture

- proteomics analyses of HSV-1 and VACV skin infections

Ethics Approval We are submitting an Ethics application to the IRAS for Research Ethics Committee (REC) for approval. This will be ready by year 2, when the student will be expected to start some work in skin tissues.

Research and Policy outputs:

Key output of this project will be a better understanding of how different skin viruses replicate in skin and identification of inhibitors that could pave the way for future development of broad-spectrum antivirals.

References:

- Jones M, Dry IR, Frampton D, Singh M, Kanda RK, Yee MB, et al. RNA-seq Analysis of Host and Viral Gene Expression Highlights Interaction between Varicella Zoster Virus and Keratinocyte Differentiation. PLOS Pathogens 2014;10:e1003896.

- Tommasi C, Breuer J. The Biology of Varicella-Zoster Virus Replication in the Skin. Viruses 2022;14:982.

- Tommasi C, Rogerson C, Depledge DP, Jones M, Naeem AS, Venturini C, et al. Kallikrein-Mediated Cytokeratin 10 Degradation Is Required for Varicella Zoster Virus Propagation in Skin. J Invest Dermatol 2020;140:774-784.e11.

Environment:

The student will work within the UCL Great Ormond Street Institute of Child Health (UCL GOS ICH), with the Breuer research group and will join an international and highly collaborative environment. Within Professor Breuer’s group Dr Tommasi is working on VZV skin infection, two post-doctoral researchers are working on SARS-CoV-2 and other respiratory viruses and a post-doctoral researcher working on developing novel metagenomic methods. In addition there are a further 4 computational post-doctoral researchers working on the evolutionary genomics of SARS-CoV-2, CMV, EBV and norovirus, a Henry Wellcome Fellow working on development of new metagenomic computational methods and one PhD student working on pathogen metagenomics. In addition, there are two wet lab post-doctoral researchers working on development of metagenomics and the pathogenesis of CMV and EBV.

The student will learn about key aspects of HSV-1, VACV and monkeypox skin replication.

This Studentship presents a unique opportunity to conduct supervised research at and be a part of the research community, being an integral part of the exciting and thriving research team.

About you

Applicants should have, or expect to receive an upper second-class Bachelor’s degree, with a Master’s degree (or equivalent work experience) in a relevant discipline or an overseas qualification of an equivalent standard.

Eligibilty 

This studentship covers the cost of tuition fees based on the UK (Home) rate. Non-UK students can apply but will have to personally fund the difference between the UK (Home) rate and the Overseas rate where they are not eligible for UK fee status.

The student will receive a starting stipend of £20,622 per annum. The studentship also covers the cost of tuition fees based on UK fee status.

How to Apply 

Enquiries regarding the post can be made to Dr Cristina Tommasi (cristina.tommasi.13@ucl.ac.uk).

To apply, please send a current CV including the contact details of two professional referees as well as a 1-sided A4 cover letter to Dr Cristina Tommasi (cristina.tommasi.13@ucl.ac.uk).

Closing deadline for applications: 09:00 Thursday 22nd February 2024.

Interview date 11th March 2024.

Applications that are submitted without following the correct application process will not be considered. The successful applicant will then be required to apply to and register on the Child Health research degree to take up the studentship.