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Kinesin-mediated transport of Marek’s disease virus


Project Description

Marek's disease is a fatal, highly contagious, neoplastic disease affecting chickens. It is caused by an alphaherpesvirus called Gallid herpesvirus-2 or Marek's Disease Virus (MDV). Advancing our understanding of MDV by identifying and characterising virus-host interactions will enable us to develop interventions that limit the transmission of MDV. This proposal focuses on the intracellular transport of MDV. Being a DNA virus, MDV needs to reach the nucleus of the host cell in order to replicate and newly formed viral capsids egress via the ER and Golgi for envelopment back to the plasma membrane to infect neighbouring cells. With a diameter of 200-300nm, MDV is too large to efficiently diffuse through the cytoplasm and therefore has to exploit the host cytoskeleton and associated molecular motors for its transport. There is currently no published information on MDV transport. In our work leading up to this proposal, we have confirmed that MDV transport depends on the microtubule cytoskeleton. Furthermore, we implicated dynein and five motors of the kinesin-3 family in MDV transport. In the proposed work we aim to identify how MDV interacts with these motors. To do this, we will identify viral proteins that interact with these motors using proximity-dependent biotinylation and mass spectrometry (BioID). We will then express domains of viral candidate proteins and analyse their binding to kinesin tails with the aim to map the interaction surfaces on both the kinesin and the viral proteins. Finally, we will aim to overexpress minimal domain or peptide sequences in the host cells to test whether these are able to interfere with viral transport. Alternatively, we will explore motor protein truncations that lack the viral binding sites. While motor transport is essential especially for neuronal function and mutations of kinesin-3 motors lead to defects in myelination and ataxias in humans and animals, the heterozygous state of a KIF1C mutation is associated with a better score for muscular development, explaining its prevalence in the French Charolais breed. Thus, it might be valuable to explore mild motor mutations in chicken that might both limit MDV spread and enhance meat production.

The student will be primarily based at the Centre for Mechanochemical Cell Biology (http://mechanochemistry.org/) at University of Warwick and trained in molecular biology, protein biochemistry and cell biology techniques including imaging-based reconstitution experiments and live cell imaging. They will participate in regular meetings with industrial partner Aviagen UK Ltd (http://eu.aviagen.com/) and collaborators at The Pirbright Institute. The student will complete a placement with the Research & Development team at Aviagen in Edinburgh. Aviagen UK Ltd is the world's leading poultry breeding company and invests heavily in research focused on delivering balanced progress in both broiler and breeder traits. During the placement, the student will learn modern broiler breeding strategies and analyse genomic and phenotypic data of commercial chicken breeds for polymorphisms in molecular motor genes.

Funding Notes

Studentship includes: fees, a tax free stipend of at least £15,009 p.a (to rise in line with UKRI recommendation); a travel allowance in year 1; a travel / conference budget; a generous consumables budget and use of a MacBook Pro for the duration of the programme.

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