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Understanding virus-host interactions by analysing diversity in viral and cell populations


Project Description

A collaboration between The Pirbright Institute and the MRC-University of Glasgow Centre for Virus Research.

Many RNA viruses introduce errors in their viral genome during replication. Such viruses therefore exist as genetically variable populations which facilitates rapid evolution and successful infection. Viruses in the picornavirus family are amongst the simplest mammalian viruses, consisting of a single molecule of RNA enclosed in a non-enveloped protein capsid and therefore provide good models to understand viral population diversity. Despite their simplicity they are also responsible for significant diseases of humans (e.g. polio, common cold) and livestock (foot-and-mouth disease). Viral population diversity can be examined by deep sequencing and several existing studies have established that diversity is required for pathogenic phenotype in vivo. Our preliminary data indicates a requirement for viral population diversity in order for foot-and-mouth disease virus (FMDV) to overcome the interferon system in primary cell cultures.

Cells also exist as populations with phenotypic variation, both in tissues in vivo and in cultures in vitro. Variation in cell populations can be characterised by bulk RNA sequencing (RNAseq) of sub-populations or more recently by single cell sequencing (scRNAseq) of many individual cells. In addition to the expected variation in primary cell cultures, studies by us (and others) have also shown that even within continuous cell lines the population of cells displays a range of susceptibility to virus infection with some cells in a population resistant to infection, i.e., they are naturally less able to support replication of the virus.

This project will combine studies in these aspects of virus and cell variation with the hypothesis that diversity in virus and cell populations contributes to the outcome of infection. Objectives of this study:
- To understand the role of viral population diversity in overcoming innate barriers to cellular infection.
- To understand the differences in cell populations that account for variation in susceptibility of cells to virus infection.

Example approaches available include: viruses engineered to have altered error rates to manipulate population diversity; GFP reporter viruses to measure replication in individual live cells; creating cell populations containing genome wide gene knock out by CRISPR; use of bioinformatics software such as Linux, Python, R, Monocle, SEURAT and SCUBA.

This multi-disciplinary project will expose the student to the research environments at both Pirbright and the Centre for Virus Research and will develop expertise in both virology/molecular laboratory work and the bioinformatics/computational approaches used to analyse the laboratory-generated data. Experience in virology and bioinformatics/computational biology will be an advantage.

TO APPLY: Full details of how to apply can be found on our website - click Visit Website.
For enquiries regarding the application process please email Admissions Enquiries - click Email Now.
For informal enquiries regarding this project please email the project supervisors noted above.

Funding Notes

This is a fully funded studentship open to science graduates with, or who anticipate obtaining, at least 2.1 or equivalent in relevant biological subject in undergraduate degree, or a Masters degree - subject to university regulations. Open to UK students and eligible EU students who qualify for home-rated fees - see Residential Eligibility Guidelines on website for details. Eligible students will receive minimum annual stipend of £15,009 plus cost of living top-up of £2,200; university registration fees will be paid. Students without English as first language must provide evidence of IELTS score of 7.0, no less than 6.5 in subsections.

References

• Poliovirus Intrahost Evolution Is Required to Overcome Tissue-Specific Innate Immune Responses. Nat Commun 8 (1), 375 2017. Yinghong Xiao, Patrick Timothy Dolan, Elizabeth Faul Goldstein, Min Li, Mikhail Farkov, Leonid Brodsky, Raul Andino.
• Foot-and-mouth Disease Virus Type O Specific Mutations Determine RNA-dependent RNA Polymerase Fidelity and Virus Attenuation. Virology 518, 87-94 May 2018. Chen Li , Haiwei Wang, Tiangang Yuan, Andrew Woodman, Decheng Yang, Guohui Zhou, Craig E Cameron, Li Yu
• Ultra-deep sequencing for the analysis of viral populations. Current Opinion in Virology Volume 1, Issue 5, November 2011, Pages 413-418. Niko Beerenwinkel, Osvaldo Zagordi
• Mapping the Evolutionary Potential of RNA Viruses. Cell Host Microbe 23 (4), 435-446 2018. Patrick T Dolan, Zachary J Whitfield, Raul Andino
• The Use of Single-Cell RNA-Seq to Understand Virus-Host Interactions. Curr Opin Virol 29, 39-50 Apr 2018. Sara Cristinelli, Angela Ciuffi

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