Molecular mechanisms and physiological consequences of bacterial virulence proteins.

About the project

About the Project Many intracellular bacterial pathogens deliver virulence (effector) proteins through dedicated secretion systems into mammalian host cells. These enable bacterial growth and disease progression and often act by subverting the host’s innate immune response, which would normally protect the infected cell. The Thurston Group want to understand the host and pathogen determinants that impact the outcome of bacterial infections. We therefore study how Salmonella and Burkholderia , two Gram-negative intracellular bacteria, manipulate innate immune signaling via the action of their virulence proteins. We combine microbiology, cell biology, biochemistry and structural biology to understand host-pathogen interactions from molecular mechanism to infection outcome. Through these studies we have uncovered effector functions that are often mediated by unusual biochemical activities. For example, we are investigating the mechanism by which SteE, a virulence effector from Salmonella , co-opts the host kinase GSK3, changing its amino acid and substrate specificity to drive a change in the status of the infected macrophage (Ref 1,2 and 3). Our recent work on Burkholderia then uncovered how the secreted effector, TssM, is a dual specificity enzyme that reverses the non-canonical ubiquitylation of bacterial lipopolysaccharide by the recently described host immune sensor RNF213 (Ref 4) providing detailed information on one mechanism that enables Burkholderia to be a silent evader of the host cell cytosol. Building on these studies, and other work where we identified a new Salmonella effector (Ref 5), the aim of this PhD is to define, in molecular detail, new roles of bacterial effectors during infection. Long-term, these findings might inform new therapeutics to combat bacterial infections.

Research areas