Small GTPase signalling networks and subversion by pathogenic bacteria

Mammalian cells polymerise actin filaments at the membrane to create a driving force for cells to move, remodel their architecture and divide, and to provide a structural framework that defines cell shape and polarity. The formation of actin structures at the membrane requires a network of actin machineries that are controlled through master regulators of the actin cytoskeleton known as Rho GTPases (20 isoforms).
A central paradigm in bacterial pathogenicity is Rho GTPase subversion by an enormous repertoire of pathogen-encoded virulence proteins that are injected into the target host cell. We recently uncovered how bacterial effectors hijack co-incident lipid and GTPase signals that cooperate to facilitate infection, e.g. Salmonella uptake into host cells (Humphreys et al, Cell Host Microbe, 2012, Humphreys et al, PNAS, 2013). This has opened my eyes to the fact that while we know many of the Rho targets, we do not know how the components interact with each other nor how virulence proteins manipulate the complex Rho cytoskeleton networks in the membrane environment.
The interdisciplinary PhD project will combine live cell imaging of the actin cytoskeleton, infection biology and biochemical reconstitution of virulence-driven actin polymerisation to understand how virulence effectors function at the membrane and hijack Rho cytoskeleton networks during infection. This is especially important given the health threat posed to humans and farmed food chain animals by bacterial pathogens that continue to develop multidrug resistance. Understanding the basis of disease has the potential to identify new therapeutic targets and augment our anti-infectives arsenal.