We combine microbiology, cell biology, biochemistry and X-ray crystallography to better understand bacterial virulence factors and host immunity. We focus on two human pathogens that occupy different niches within cells. Salmonella is vacuole-adapted whereas Burkholderia pseudomallei complex bacteria replicate in the cytosol. Both impose a significant human and social-economic burden. Our goal is to understand the host and pathogen determinants that impact the intracellular fate of these bacteria.
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Wild-type Burkholderia (red) are detected by immune sensor RNF213 (green) inside mammalian cells.
Burkholderia Virulence factor TssM is a deubuitylase that mediates evasion of RNF213-directed immunity.
We want to understand the molecular mechanisms that determine the outcome of a bacterial infection. We study both the cell-intrinsic innate immune mechanisms that protect against intracellular bacteria and the pathogen virulence proteins (effectors) that counteract the host’s immune response. Our main pathogens or study are Salmonella, which is responsible for ~ 1 million death per year world-wide and Burkholderia, which imposes a significant human and social-economic burden in lower-middle income countries.
Using multidisciplinary approach encompassing genetics, cell biology, biochemistry and structural biology we have uncovered new functions and molecular mechanisms for effectors delivered from either Salmonella or Burkholderia. Our long-term vision is to identify new effector biochemistry in diverse bacterial pathogens, driving forward our fundamental understanding of pathogenesis. With this knowledge and in combination with synthetic biology we then hope to inform the development of new therapeutics to prevent bacterial disease.
2024
Modulation of Salmonella virulence by a novel SPI-2 injectisome effector that interacts with the dystrophin-associated protein complex.
Yu, X-J., Xie, H., Li., Y, Liu, M., Hou, R., Predeus, A.V., Perez Sepulveda, B.M., Hinton, J.C.D., Holden, D.W., Thurston, T.L.M.
mBio – 15(7):e0112824.
2024
Bacterial esterases reverse lipopolysaccharide ubiquitylation to block host immunity.
Szczesna, M., Huang , Y., Lacoursiere, R.E., Bonini, F., Pol, V., Koc, F., Ward, B., Geurink, P.P., Pruneda, J.N., Thurston, T.L.M.
Cell Host Microbe – 32(6):913-924.e7.
2020
Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization.
Panagi, I., Jennings, E., Zeng, J., Günster, R.A., Stones, C.D., Mak, H., Jin, E., Stapels, D.A.C., Subari, N.Z., Pham, T.H.M., Brewer, S.M., Ong, S.Y.Q., Monack D.M., Helaine, S., Thurston, T.L.M.
Cell Host Microbe – 27(1):41-53.e6.
2018
Structure-function analyses of the bacterial zinc metalloprotease effector protein GtgA uncover key residues required for deactivating NF-κB.
Jennings, E., Esposito, D., Rittinger, K., Thurston, T.L.M.
J Biol. Chem. – 293(39):15316-15329.
2017
SseK1 and SseK3 Type III Secretion System Effectors Inhibit NF-κB Signaling and Necroptotic Cell Death in Salmonella-Infected Macrophages.
Günster, R.A., Matthews, S.A., Holden, D.W., Thurston, T.L.M.
Infect Immun. – 85(3):e00010-17.