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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.

Summary Focus: Mucosal inflammation, host: pathogen interactions, and cancer biology
One or more keywords matched the following items that are connected to McCormick, Beth
Item TypeName
Academic Article Cadaverine prevents the escape of Shigella flexneri from the phagolysosome: a connection between bacterial dissemination and neutrophil transepithelial signaling.
Academic Article Identification of hepoxilin A3 in inflammatory events: a required role in neutrophil migration across intestinal epithelia.
Academic Article Interactions of intestinal epithelial cells with bacteria and immune cells: methods to characterize microflora and functional consequences.
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 Multidrug resistance-associated transporter 2 regulates mucosal inflammation by facilitating the synthesis of hepoxilin A3.
Academic Article A new understanding of enteroaggregative Escherichia coli as an inflammatory pathogen.
Academic Article Events at the host-microbial interface of the gastrointestinal tract. II. Role of the intestinal epithelium in pathogen-induced inflammation.
Academic Article The role of neutrophils in the event of intestinal inflammation.
Academic Article Enteroaggregative Escherichia coli promotes transepithelial migration of neutrophils through a conserved 12-lipoxygenase pathway.
Academic Article The fimbriae of enteroaggregative Escherichia coli induce epithelial inflammation in vitro and in a human intestinal xenograft model.
Academic Article Control of neutrophil inflammation at mucosal surfaces by secreted epithelial products.
Concept Inflammation Mediators
Concept Inflammation
Academic Article Systemic disease during Streptococcus pneumoniae acute lung infection requires 12-lipoxygenase-dependent inflammation.
Academic Article PERP, a host tetraspanning membrane protein, is required for Salmonella-induced inflammation.
Academic Article Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis.
Academic Article Enteroaggregative Escherichia coli Adherence Fimbriae Drive Inflammatory Cell Recruitment via Interactions with Epithelial MUC1.
Academic Article Cytosolic Phospholipase A2a Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection.
Academic Article Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis.
Academic Article Bacterial-induced hepoxilin A3 secretion as a pro-inflammatory mediator.
Academic Article Alzheimer's Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway.
Academic Article Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells.
Academic Article Inflammation-type dysbiosis of the oral microbiome associates with the duration of COVID-19 symptoms and long COVID.
Academic Article Gut microbiota regulate Alzheimer's disease pathologies and cognitive disorders via PUFA-associated neuroinflammation.
Academic Article Microbial Metabolites Orchestrate a Distinct Multi-Tiered Regulatory Network in the Intestinal Epithelium That Directs P-Glycoprotein Expression.
Academic Article Basic Science and Pathogenesis.
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  • Inflammation