Type III Secretion System
Type III secretion systems (T3SS) is a specialized apparatus expressed by many Gram negative bacteria, including almost two dozen human pathogens. The hallmark of the T3SS is contact-dependent delivery of bacterial effector proteins directly into the cytosol of target host cells. These T3SS effector proteins mediate diverse effects on normal host cell processes, including inhibition of phagocytosis and inflammatory cytokine production. The T3SS is composed of a basal body that spans both the inner and outer membranes and a needle-like structure that extends ~60 nm from the outer membrane (see figure, right). Components of the T3SS tip complex act concertedly to form a pore in the target host cell membrane, facilitating directed translocation of effector proteins into the host cell cytosol.
T3SS inhibitor drug discovery
With increasing incidence of antibiotic resistance, development of new therapies against bacterial pathogens is essential for global public health. For example, according to the CDC, every year over 50,000 healthcare-associated Pseudomonas aeruginosa infections occur in the U.S., >6,000 of which are caused by multidrug resistant strains.
The T3SS represents an excellent drug target because it is externally accessible to small molecules and enables virulence of Pseudomonas, Salmonella, Chlamydia, Yersinia, and numerous other important pathogens. We have developed a high throughput screening pipeline to discover T3SS inhibitors and have shown the robustness of our approach through pilot screens identifying three classes of compounds active against the T3SS.
We collaborate with the Lokey, Crews, and MacMillan labs in the UCSC Chemistry and Biochemistry departments as well as with the Linington lab at Simon Fraser University in Canada to identify natural products and natural product-inspired compounds with T3SS inhibitory activity. See the following talk given by our lab and collaborators concerning this project: Interdisciplinary Science Symposium
Yersinia virulence factors
The Ysc T3SS is critical for the pathogenicity of the enteropathogic Yersinia species Y. pseudotuberculosis and Y. enterocolitica as well the close related species Y. pestis, which causes plague. However, type III secretion is metabolically burdensome and correlates with growth arrest. In addition, T3SS activity can lead to host innate immune recognition. Therefore, Yersinia must tightly control T3SS expression and deployment to optimize fitness in the mammalian host. We identified the iron-sulfur cluster coordinating transcription factor IscR as a critical regulator of the Yersinia T3SS. We are currently investigating how Yersinia senses environmental cues to control the T3SS and other important virulence factors.