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A newly discovered protein encoded by enteroviruses: from mechanism to application

  • Full or part time
  • Application Deadline
    Wednesday, January 01, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Enteroviruses have single-stranded RNA genomes of ~7.4 kb. For the last 5 decades, enteroviruses were thought to encode all of their proteins in a single long open reading frame (ORF) that spans most of the genome and is translated as a polyprotein which is subsequently processed by virus-encoded proteases to produce 11 viral proteins. However, we recently showed that many enteroviruses encode an additional protein in an upstream open reading frame (uORF). Knocking out expression of the uORF protein (termed “UP”, Upstream Protein) attenuates virus growth at late stages of infection in human intestinal organoids but not in standard cell culture systems, suggesting a specific role for UP during establishment of infection in gut epithelia in the initial stages of virus invasion into susceptible hosts. This work was recently published in Nature Microbiology (Lulla et al., 2019, PMID 30478287).
The discovery of a new protein opens a whole new research direction in enterovirus molecular biology and pathogenesis. Understanding the precise role(s) of UP in different enterovirus species may also lead to new virus control strategies. However, many very important questions remain unanswered, such as how the UP protein facilitates release of virus from membranous compartments specific to gut epithelial cells, why some enteroviruses have UP whereas others do not, UP localization and biophysical properties, the role of gut epithelial cell type and origin, how UP affects virus-host interactions, and how UP expression is controlled. The PhD project will investigate the function of the UP protein and potential virus vaccine strategies.

Funding Notes

Funding* will cover the student’s stipend at the current Research Council rate and University Fees. The studentships will be funded for three years in the first instance subject to eligibility**, with the possibility of additional funding in the fourth year depending on circumstances.

**The studentships are available to students who qualify for Home/EU fees

Applications from ineligible candidates will not be considered.

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References

Lulla V*, Dinan AM, Hosmillo M, Chaudhry Y, Sherry L, Irigoyen N, Nayak KM, Stonehouse NJ, Zilbauer M, Goodfellow I, Firth AE* (2019) An upstream protein-coding region in enteroviruses modulates virus infection in gut epithelial cells. Nature Microbiology 4:280-292.
Napthine S, Ling R, Finch LK, Jones JD, Bell S, Brierley I*, Firth AE* (2017) Protein-directed ribosomal frameshifting temporally regulates gene expression. Nature Communications 8:15582.
Lulla V, Firth AE (2019) A hidden gene in astroviruses encodes a cell-permeabilizing protein involved in virus release. bioRxiv 661579; doi: https://doi.org/10.1101/661579.

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