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Understanding the importance of the PI3K pathway in modulating influenza virus replication in chickens and ducks


Project Description

Avian influenza virus (AIV) is a pathogen that causes significant economic and welfare issues for the poultry industry. In addition, there is the additional concern that avian influenza strains may be able to cross the species barrier and infect humans. Increasing our knowledge about AIV is fundamental to devising practical and effective control strategies for AIV in avian species.

Ducks and chickens often have different clinical disease manifestations to the same influenza A virus (IAV) isolate. Previous work at Nottingham university has demonstrated that infected duck cells underwent rapid cell death and thus limited the spread of virus, whereas chicken cells survived for longer and replicated the virus to significantly higher titres. The phosphoinositide 3-kinase (PI3K) cell-signalling pathway is a key regulator of cell survival and is often activated by viruses to promote survival following infection. Our previous work has demonstrated that IAV activates the PI3K pathway in chicken cells but not in duck cells. We have also shown that the kinetics and pattern of induction of the PI3K pathway is IAV strain dependant in chicken cells. Some strains induce the phosphorylation of AKT at 6 hours whereas others have a delay to 24 hours post infection which may influence the cell survival and virus yield. It has been shown in human cells that activation of PI3K pathways was mediated by the IAV NS1 protein which binds directly to the p85beta regulatory subunit of PI3K and causes PI3K-dependent phosphorylation of Akt, preventing premature apoptosis. Our analysis of the chicken and duck the p85beta regulatory subunit sequence shows several differences that may influence the ability of NS1 to bind to and activate this protein in a host dependant manner, which suggests a possible mechanism for the differences in clinical outcome observed.

The hypothesis of this project is that differential activation of the PI3K during influenza virus infection impacts the disease phenotype in avian species. The studentship will investigate the following research questions that relate to the hypothesis; 1. What viral characteristics result in the strain-related differences in PI3K pathway activation that have been observed and 2. What impact the differences in the chicken and duck PI3K-p85 subunits have on the activation of the PI3K pathway by influenza viruses.

A combination of classical virology techniques including reverse genetics for influenza viruses as well as cutting edge genetic editing of cells using CRISPR will be utilised in this project. Training in skills including bioinformatic analysis of viral sequences and PI3K-p85 sequences will be performed and the preparation of samples and analysis of mass spectroscopy data will also be offered in this project. This studentship has the advantage of spending time in two thriving and inspiring science organisations; The Pirbright Institute and The University of Nottingham which offers multiple opportunities to the student. We are looking for an enthusiastic, team player who wants to learn and be part of our research teams.

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 applicants with (or who anticipate obtaining) minimum of 2:1 undergraduate degree, or minimum of 2:2 undergraduate degree and Master's degree, in biological or veterinary sciences or similar. Open to UK 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 allowance whilst based at Pirbright; home-rated university registration fees will be paid. Students without English as first language must provide evidence of IELTS 6.5, no less than 6.0 in subsections.

References

[1] J. Ayllon, A. Garcia-Sastre, B.G. Hale, Influenza A viruses and PI3K: are there time, place and manner restrictions?, Virulence 3(4) (2012) 411-4.
[2] J. Ayllon, B.G. Hale, A. Garcia-Sastre, Strain-specific contribution of NS1-activated phosphoinositide 3-kinase signaling to influenza A virus replication and virulence, J Virol 86(9) (2012) 5366-70.
[3] B.G. Hale, I.H. Batty, C.P. Downes, R.E. Randall, Binding of influenza A virus NS1 protein to the inter-SH2 domain of p85 suggests a novel mechanism for phosphoinositide 3-kinase activation, J Biol Chem 283(3) (2008) 1372-80.
[4] B.G. Hale, D. Jackson, Y.H. Chen, R.A. Lamb, R.E. Randall, Influenza A virus NS1 protein binds p85beta and activates phosphatidylinositol-3-kinase signaling, Proc Natl Acad Sci U S A 103(38) (2006) 14194-9.
[5] B.G. Hale, R.E. Randall, PI3K signalling during influenza A virus infections, Biochem Soc Trans 35(Pt 2) (2007) 186-7.
[6] S.V. Kuchipudi, S.P. Dunham, K.C. Chang, DNA microarray global gene expression analysis of influenza virus-infected chicken and duck cells, Genom Data 4 (2015) 60-4.
[7] S.V. Kuchipudi, S.P. Dunham, R. Nelli, G.A. White, V.J. Coward, M.J. Slomka, I.H. Brown, K.C. Chang, Rapid death of duck cells infected with influenza: a potential mechanism for host resistance to H5N1, Immunol Cell Biol 90(1) (2012) 116-23.

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