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Beth McCormickB.A. University of New Hampshire
Ph.D. University of Rhode Island
Post-doctoral training Harvard Medical School

Research Summary:

Work in my laboratory is centered around three major research programs: Mucosal inflammation, host:pathogen interactions, and cancer biology.

Image 1The objective of the mucosal inflammatory program is to investigate the molecular mechanisms by which bacterial pathogens induce mucosal inflammation at sites of the intestinal and respiratory epithelium. This work is based on longstanding pathologic observations that attachment of an array of bacterial pathogens to epithelial surfaces is accompanied by recruitment of host defense cells, as manifested by neutrophil infiltration of the epithelium. While neutrophils and their responses in the context of an inflammatory response are integral to the control of bacterial infection, when their responses become excessive or unregulated, injury to the host tissues ensues. To understand what goes awry under pathologic conditions, we originally used Salmonella typhimurium as a prototypical enteric pathogen to study the transepithelial migration of neutrophils across intestinal epithelia, a hallmark of gastroenteritis. This research effort has been expanded to include the following intestinal and lung pathogens: Shigella flexneri, E. coli, Pseudomonas aeruginosa, and S. pneumoniae. In response to these pathogens we have discovered a novel inflammatory signaling cascade in which epithelial cells lining mucosal surfaces release the potent neutrophil chemoattractant hepoxilin A3, (HXA3). HXA3 functions as the “gate keeper” of the mucosal epithelium, as it emanates from the site of infection to establish a chemotactic gradient that guides neutrophils across mucosal surfaces. We are now investigating the mechanisms that orchestrate the synthesis/release of HXA3 for the design of more targeted and effective anti-inflammatory therapies for the treatment of infectious, allergic, and idiopathic mucosal inflammatory conditions (i.e., salmonellosis, shigellosis, inflammatory bowel diseases, pneumonia, cystic fibrosis, and chronic obstructive pulmonary disease).

SopA StructureThe second research program in my laboratory is centered on the study of host-pathogen interactions. Specifically, we investigate strategies used by enteric and respiratory pathogens to induce proinflammatory responses. Using S. typhimurium as an example, we have uncovered a novel mechanism by which this pathogen sabotages host defense mechanisms. Salmonella tricks the host into synthesizing and secreting the apoptotic enzyme caspase-3, diverting this host enzyme to its own use. The Salmonella effector protein SipA has amino acid motifs that are recognized by caspase-3, which cleaves the bacterial protein into active virulence effectors: one stimulates actin polymerization to help cell entry and the other induces inflammation. If the caspase motif contains a single-point mutation, then virulence is lost in mouse models of infection. This straregy isn’t limited to SipA. Other proteins that are injected by Salmonella, such as SopA (see crystal structure) and those from other gut bacteria like E. coli and Shigella flexneri, also carry targets for caspase-3, demonstrating the broad significance of this finding. This discovery unveils a new paradigm in the field of bacterial pathogenesis and opens the door to novel investigation on the tactics used by bacterial pathogens to promote disease.

Colonic TumorThe third research program in my laboratory is focused on cancer biology. My original interest in this field of study was cultivated by the observation that Salmonella is able to preferentially locate to sites of tumor growth (achieving tumor/normal tissue ratios of approximately 1,000:1). Work in my laboratory has shown that Salmonella causes a profound reduction on the multidrug resistance (MDR) transporter P-glycoprotein (Pgp) in colon cancer cells. Pgp over-expression is one form of the MDR phenotype that is commonly acquired by cancer patients initially responsive to chemotherapy. We are interested in uncovering the mechanism used by Salmonella to downregulate Pgp. The ultimate goal of this work is to exploit Salmonella for the development of a new and robust class of multidrug resistance inhibitors designed as an adjuvant to chemotherapeutics for cancers that are known to express high levels of Pgp, such as colorectal cancers and breast cancer.

One or more keywords matched the following items that are connected to McCormick, Beth
Item TypeName
Academic Article Requirement of the Shigella flexneri virulence plasmid in the ability to induce trafficking of neutrophils across polarized monolayers of the intestinal epithelium.
Academic Article The use of transepithelial models to examine host-pathogen interactions.
Academic Article nadA and nadB of Shigella flexneri 5a are antivirulence loci responsible for the synthesis of quinolinate, a small molecule inhibitor of Shigella pathogenicity.
Academic Article Distinct isoforms of phospholipase A2 mediate the ability of Salmonella enterica serotype typhimurium and Shigella flexneri to induce the transepithelial migration of neutrophils.
Academic Article Shigella flexneri type III secretion system effectors OspB and OspF target the nucleus to downregulate the host inflammatory response via interactions with retinoblastoma protein.
Academic Article Shigella gets captured to gain entry.
Academic Article OspF and OspC1 are Shigella flexneri type III secretion system effectors that are required for postinvasion aspects of virulence.
Academic Article The NleE/OspZ family of effector proteins is required for polymorphonuclear transepithelial migration, a characteristic shared by enteropathogenic Escherichia coli and Shigella flexneri infections.
Academic Article Saccharomyces boulardii interferes with Shigella pathogenesis by postinvasion signaling events.
Concept Shigella
Concept Shigella flexneri
Academic Article Bacterial-enterocyte crosstalk: cellular mechanisms in health and disease.
Academic Article Shigella depends on SepA to destabilize the intestinal epithelial integrity via cofilin activation.
Academic Article Shigella flexneri Interactions with the Basolateral Membrane Domain of Polarized Model Intestinal Epithelium: Role of Lipopolysaccharide in Cell Invasion and in Activation of the Mitogen-Activated Protein Kinase ERK.
Academic Article GEF-H1 mediated control of NOD1 dependent NF-kappaB activation by Shigella effectors.
Academic Article SepA Enhances Shigella Invasion of Epithelial Cells by Degrading Alpha-1 Antitrypsin and Producing a Neutrophil Chemoattractant.
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  • Shigella