Research in our laboratory is focused on understanding how bacterial pathogens co-opt eukaryotic host cell processes to promote infection and cause disease. Our work focuses on studying specialized secretion systems that numerous gram-negative bacteria utilize to deliver tens of proteins into host cells. We are interested in my facets of these complex secretory systems including (1) how the bacteria define substrates of the secretion machines and deliver them into mammalian cells and (2) how these translocated proteins act to subvert eukaryotic cellular biology to promote the establishment of an infection, particularly how they enable intracellular pathogens like Shigella to escape into the cytosol, spread from cell-to-cell and suppress host innate immune signaling pathways. In addition, (3) we are currently reengineering the bacterial secretion systems to deliver therapeutic molecules rather than virulence proteins into host cells in hopes of developing novel ways to treat a variety of human diseases.
We investigate these questions using multidisciplinary approaches including those based in molecular genetics, cell-biology and biochemistry. In addition, since many of the secreted proteins, referred to as effectors, target cellular processes conserved among all eukaryotes we use a variety of model systems including yeast and mammalian cell culture to study the effectors. Our lab has pioneered the development of a yeast systems-biology approach to identify conserved eukaryotic proteins and processes targeted by the effectors. For this approach we have developed robotic-based functional genomic assays as well as a novel yeast-based assay for visualizing protein interactions in living cells- the Protein Interaction Platform (PIP) assay. In addition, we are currently working on a bottom-up approach bacterial based approach for studying the roles of individual effectors in pathogenesis. The majority of our current work is focused on studying effectors from enteric gram-negative pathogens with an emphasis on Shigella flexneri although recent work has led us to begin to study endosymbionts.
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