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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 Unmasking of intestinal epithelial lateral membrane beta1 integrin consequent to transepithelial neutrophil migration in vitro facilitates inv-mediated invasion by Yersinia pseudotuberculosis.
Academic Article A functional cra gene is required for Salmonella enterica serovar typhimurium virulence in BALB/c mice.
Academic Article Salmonella enterica serovar typhimurium-dependent regulation of inducible nitric oxide synthase expression in macrophages by invasins SipB, SipC, and SipD and effector SopE2.
Academic Article The GTPase Rac1 selectively regulates Salmonella invasion at the apical plasma membrane of polarized epithelial cells.
Academic Article A secreted Salmonella protein induces a proinflammatory response in epithelial cells, which promotes neutrophil migration.
Academic Article The inflammation-associated Salmonella SopA is a HECT-like E3 ubiquitin ligase.
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 The two-component sensor response regulator RoxS/RoxR plays a role in Pseudomonas aeruginosa interactions with airway epithelial cells.
Academic Article Salmonella pathogenesis and processing of secreted effectors by caspase-3.
Academic Article The ERM protein, ezrin, regulates neutrophil transmigration by modulating the apical localization of MRP2 in response to the SipA effector protein during Salmonella Typhimurium infection.
Academic Article Salmonella typhimurium SipA-induced neutrophil transepithelial migration: involvement of a PKC-alpha-dependent signal transduction pathway.
Academic Article Salmonella typhimurium attachment to human intestinal epithelial monolayers: transcellular signalling to subepithelial neutrophils.
Academic Article Surface attachment of Salmonella typhimurium to intestinal epithelia imprints the subepithelial matrix with gradients chemotactic for neutrophils.
Academic Article Caenorhabditis elegans-based screen identifies Salmonella virulence factors required for conserved host-pathogen interactions.
Academic Article Identification of the Salmonella enterica serotype typhimurium SipA domain responsible for inducing neutrophil recruitment across the intestinal epithelium.
Academic Article Salmonella enterica Typhimurium SipA induces CXC-chemokine expression through p38MAPK and JUN pathways.
Academic Article Salmonella effectors: important players modulating host cell function during infection.
Academic Article Salmonella effector proteins and host-cell responses.
Concept Bacterial Proteins
Academic Article Escherichia coli F-18 phase locked 'on' for expression of type 1 fimbriae is a poor colonizer of the streptomycin-treated mouse large intestine.
Academic Article Bacterial secreted effectors and caspase-3 interactions.
Academic Article PERP, a host tetraspanning membrane protein, is required for Salmonella-induced inflammation.
Academic Article The type three secreted effector SipC regulates the trafficking of PERP during Salmonella infection.
Academic Article A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours.
Academic Article Can a nanoparticle that mimics Salmonella effectively combat tumor chemotherapy resistance?
Academic Article Shigella depends on SepA to destabilize the intestinal epithelial integrity via cofilin activation.
Academic Article SipA Activation of Caspase-3 Is a Decisive Mediator of Host Cell Survival at Early Stages of Salmonella enterica Serovar Typhimurium Infection.
Academic Article Caspase-3 cleavage of Salmonella type III secreted effector protein SifA is required for localization of functional domains and bacterial dissemination.
Academic Article Pneumolysin Induces 12-Lipoxygenase-Dependent Neutrophil Migration during Streptococcus pneumoniae Infection.
Academic Article SepA Enhances Shigella Invasion of Epithelial Cells by Degrading Alpha-1 Antitrypsin and Producing a Neutrophil Chemoattractant.
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  • Bacterial Proteins