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Viral and Cellular Requirements for Formation of the Foot-And-Mouth Disease Virus Capsid

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  • Full or part time
    Dr Tuthill
    Prof Curry
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Principal Supervisors: Toby Tuthill, The Pirbright Institute; Stephen Curry, Imperial College London; Graham Belsham, DTU-Vet

Foot-and-mouth disease virus (FMDV) causes an economically devastating disease of livestock. In the developing world it contributes to poverty and reduced food production. In the developed world, countries that are normally disease-free can face enormous losses during outbreaks as in the UK in 2001. Control of FMD is difficult because current vaccines suffer from a delay before immunity develops and a short duration of immunity. An alternative strategy for emergency control is the use of antiviral drugs, as such treatments have the potential to be fast acting and bridge the delay until vaccine-mediated immunity is in place.

The FMDV capsid is the essential outer shell that protects the viral genome when it is released from the cell. Capsid assembly proceeds from monomeric protein precursors, via pentameric intermediates, to complete non-enveloped icosahedral capsids. The early stages of capsid assembly are known to require myristoylation of the precursor and its proteolytic processing by a viral protease. We have recent preliminary data also showing a requirement for the cellular chaperone machinery in FMDV pentamer assembly. This and studies with other related viruses suggest that interactions between capsid precursors and cellular proteins are required for the early stages of virus assembly.

This project will generate fundamental information about how FMDV capsid precursors interact with each other and with cellular proteins to bring about capsid assembly. Understanding these interactions will provide knowledge underpinning the development of novel antiviral reagents and contribute to new strategies for making more stable vaccines. The impact of this work will not be limited to FMDV but could also contribute to the future development of antivirals against related human viruses in the picornavirus family.
Specific objectives include:

1. Identification of residues at viral subunit interfaces required for FMDV capsid assembly, using structure-guided mutagenesis (with Prof. Stuart, University of Oxford), reverse genetics, and capsid assembly assays.
2. Determining the role of cellular chaperones in FMDV capsid assembly by testing effect of pharmacological inhibitors on virus growth and capsid assembly.
3. Characterisation of cellular proteins interacting with capsid precursors by using state of the art quantitative proteomics approaches, SILAC/immunoprecipitation and high resolution SEC (with Prof. Lamond, University of Dundee).

Funding Notes

A BBSRC fully funded project open to UK students and eligible EU students who qualify for home-rated fees in line with BBSRC criteria:
http://www.bbsrc.ac.uk/documents/studentship-eligibility-pdf/
Eligible students will receive a minimum tax-free stipend of £14,057 - university fees will be paid.
Open to science graduates (with, or who anticipate, at least a 2.1 or equivalent in a relevant biological subject in an undergraduate degree, or a Masters degree - subject to university regulations). Other first degrees considered.
Students without English as a first language must provide evidence of IELTS score of 7.0, no less than 6.5 in any subsections (or equivalent).

References

1. Rincon, V., et al. (2015). "Different functional sensitivity to mutation at intersubunit interfaces involved in consecutive stages of foot-and-mouth disease virus assembly." J Gen Virol 96(9): 2595-2606.
2. Gullberg, M., et al. (2014). “Sequence adaptations affecting cleavage of the VP1/2A junction by the 3C protease in foot-and-mouth disease virus-infected cells.” J Gen Virol. 95(11):2402-10.
3. Jiang, P., et al. (2014). “Picornavirus morphogenesis.” Microbiol Mol Biol Rev. 78(3):418-37. Review.
4. Goodwin, S., et al. (2009). "Foot-and-mouth disease virus assembly: processing of recombinant capsid precursor by exogenous protease induces self-assembly of pentamers in vitro in a myristoylation-dependent manner." J Virol 83(21): 11275-11282.
5. Geller, R., et al. (2007). "Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance." Genes Dev 21(2): 195-205.

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