B.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.

The 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).

The 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.

The 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.