The role of membrane trafficking and the microtubule cytoskeleton during vaccinia virus replication and spread

This 4-year PhD studentship is offered in Dr Michael Way’s Group based at the Francis Crick Institute (the Crick).

Viruses are obligate intracellular parasites that are critically dependent on their hosts to replicate and generate new progeny. To achieve this goal, viruses have evolved numerous elegant strategies to subvert and utilize the different cellular machineries and processes of their hosts. Investigating how viruses and other intracellular pathogens hijack and subvert their unwilling hosts offers a unique opportunity to obtain mechanistic insights into the regulation and function of a multitude of cellular processes. To this end, we use a combination of quantitative imaging and biochemical approaches to study vaccinia virus as a model system to interrogate the regulation and function of Src and Rho GTPase signalling networks, membrane trafficking, actin and microtubule-based transport as well as cell migration.
Vaccinia undergoes a complex replication cycle in cytoplasmic viral factories anchored near the microtubule organizing centre of the cell (Leite and Way, 2015). Viral assembly, which is still not fully understood, results in the assembly of two morphologically distinct types of virus particles, the latter of which undergoes kinesin-1 dependent microtubule transport to the plasma membrane (Leite and Way, 2015; Dodding et al., 2011). At the cell periphery, the virus promotes its release from the cell by modulating the cortical actin beneath the plasma membrane by inhibiting RhoA signaling (Yutaka et al., 2013). After fusion with the plasma membrane, extracellular virus associated with the outside of the cell recruit Eps15, intersectin-1, AP-2 and clathrin, before locally activating a Src and Abl family kinase signaling network involving Cdc42, Grb2, Nck, WIP and N-WASP to stimulate Arp2/3 complex mediated actin polymerization to enhance viral spread (Leite and Way, 2015; Abella et al., 2016; Snetkov et al., 2016).
Understanding how Vaccinia stimulates actin polymerization to enhance its spread has provided unprecedented insights into how a phosphotyrosine-based signalling network is assembled, regulated and functions at the molecular level to stimulate Arp2/3 dependent actin polymerization. By contrast, we still lack a molecular understanding how the Vaccinia hijacks membrane trafficking and the microtubule cytoskeleton and its associated motors to promote virion assembly and movement to the plasma membrane. The project will investigate the role of membrane trafficking and microtubule driven transport during the replication and spread of Vaccinia virus. The precise project will be decided on consultation with the supervisor during the interview.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2017 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE BY 12NOON GMT NOVEMBER 14TH 2016. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.
https://www.crick.ac.uk/about-us/jobs-and-study/phd-programme/