The Picking laboratory explores the molecular mechanisms by which enteric bacterial pathogens cause disease. More specifically, we examine the protein secretion systems used by important bacterial pathogens to subvert normal host cell behavior. We study these proteins in terms of their structure, function, and potential interactions with host cells.
Type III secretion system-mediated invasion of epithelial cells by Shigella
Gastrointestinal illnesses are a serious worldwide public health problem and Shigella flexneri is an important agent of infectious diarrhea. S. flexneri is a gram negative enteric bacterium that breaches the colonic epithelium via M cells to come into contact with subepithelial macrophages that attack the bacterium; however, S. flexneri escapes being killed killing by inducing macrophage apoptosis. These events provide S. flexneri with access to the basal region of the epithelial layer where it invades the epithelial cells. The resulting cytokine responses promote PMN infiltration and evoke severe localized inflammation.
S. flexneri invasion of epithelial cells is characterized by induced actin polymerization within the host cell at the point of pathogen contact. Cytoskeletal rearrangements lead to the formation of filopodia that coalesce to form membrane ruffles that surround the pathogen and trap it in a membrane-bound vacuole. Genes required for the S. flexneri invasive phenotype include the ipa genes, which encode two secreted “translocator proteins” called invasion plasmid antigens (Ipa) B and C, along with IpaD which serves as a controlling agent in type III secretion (T3S). Other required components of the Shigella T3S apparatus are encoded by the mix/spa genes, which include a “needle protein” called MxiH. For Shigella, the Ipa proteins are the major targets of the host immune response and they are therefore targets for developing new methods of preventing shigellosis.
In addition to studying the pathogenesis of Shigella spp., my group also explores protein structure function relationships for T3S proteins from other pathogens such as Salmonella spp., Burkholderia pseudomallei, Yersinia spp. and Pseudomonas aeruginosa.
- Pathogenic Microbiology