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MIBRC Research

Principal Investigators:

Bobby Cherayil, MD

Alessio Fasano, MD

Verena Göbel, MD

Bryan Hurley, PhD

Hai Ning Shi, DVM, PhD

W. Allan Walker, MD

Collaborators:

Beth McCormick, PhD

Hans-Christian Reinecker, MD

Research Lab

Beth McCormick, PhD

Professor, Harvard Medical School

Phone: (617) 726-4168
FAX: (617) 726-4172
Email: mccormic@helix.mgh.harvard.edu

Mucosal Inflammation, Host:Pathogen Interactions, and Cancer Biology

Dr. McCormick transitioned to the University of Massachusetts Medical School in 2008, where she is currently Professor and Vice Chairman of the Department of Microbiology and Physiological Systems. Work in her 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, Dr. McCormick 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 she has 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. Dr. McCormick is 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 Dr. McCormick’s laboratory is centered on the study of host-pathogen interactions, and specifically she investigate strategies used by enteric and respiratory pathogens to induce proinflammatory responses. Dr. McCormick recently made the seminal discovery that 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 strategy isn’t limited to SipA. Other proteins that are injected by Salmonella, 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 Dr. McCormick’s laboratory is focused on cancer biology. Her 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 Dr. McCormick’s 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. She is now 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.

Studying Shigella and Acute Colitis

Shigella organisms are responsible for acute bacillary dysentery, one of the most important health concerns worldwide. Dr. Beth McCormick’s laboratory has been studying the mechanisms involved in acute infectious colitis due to shigellosis.

These studies utilize the T84 cell model in a detailed examination of Shigella and enterocyte basolateral membrane interface, including signal transduction and chemokine stimulus for neutrophil migration, which is the putative mechanism of Shigella-induced pathogenesis of gut inflammation. Collaborative studies with Dr. Hans-Christian Reinecker have also suggested that S. flexneri regulates several functional components of the tight junctions, including ZO-1 and claudin-1.

Dr. McCormick’s group continues to examine in detail the molecular mechanisms involved in the modulation of tight junction proteins by S. flexneri as well as the signaling pathways involved in S. flexneri-induced PMN transepithelial cell migration. Experiments to address the effects of probiotics in inflammatory enterocyte signaling and tight junction regulation in response to S. flexneri are also performed.

These studies are conducted in a collaborative manner with Dr. Allan Walker, Dr. Reinecker, and Dr. Ciarán Kelly. Dr. Reinecker is a collaborator on a Program Project grant whose laboratory exists in the GI Unit at MGH.