PhD project

Supervisor: Teresa Thurston

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 X-ray crystallography to understand this 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). 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 2) 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 3), the aim of this PhD is to define new roles of bacterial effectors during infection. Long-term, these findings might inform new therapeutics to combat bacterial infections.

Keywords:

• Biochemistry, Cell Biology, Genetics, Immunology, Microbiology, Molecular Biology, Structural Biology

Publications:

1. Panagi I, Jennings E, Zeng Z, Günster RA, Stones CD, Mak H, Jin E, Stapels DAC, Subari NZ, Pham THM, Brewer SM, Ong SYQ, Monack DM, Helaine S, Thurston TLM. The Salmonella effector SteE converts the mammalian serine/threonine kinase GSK3 into a tyrosine kinase. Cell Host & Microbe. 2020 Jan 8;27(1):41-53.e6. doi: 10.1016/j.chom.2019.11.002. PMID: 31862381
2. Szczesna M, Huang Y, Lacoursiere RE, Bonini F, Pol V, Koc F, Ward B, Geurink PP, Pruneda JN, Thurston TLM. Bacterial esterases reverse lipopolysaccharide ubiquitylation to block host immunity. Cell Host Microbe. 2024 Jun 12;32(6):913-924.e7. doi: 10.1016/j.chom.2024.04.012. PMID: 38870903
3. Yu X-J, Xie H, Li Y, Liu M, Hou R, Predeus AV, Perez Sepulveda BM, Hinton JCD, Holden DW, Thurston TLM. Modulation of Salmonella virulence by a novel SPI-2 injectisome effector that interacts with the dystrophin-associated protein complex. mBio. 2024 Jul 17;15(7):e0112824. doi: 10.1128/mbio.01128-24. PMID: 38904384