Beth McCormick

Mucosal Immunology Laboratory, Director: W. Allan Walker

Summary of Research

My research is focused on the molecular and cellular mechanisms by which the enteric pathogens Salmonella typhimurium and Shigella flexneri induce mucosal inflammatory responses. Such inflammatory responses lead to active states of intestinal inflammation and are a hallmark feature of the disease pathophysiology of inflammatory bowel diseases such as bacterial enterocolitis, Crohn’s Disease, and ulcerative colitis. Such active states of inflammation are histologically characterized by the infiltration of neutrophils across the intestinal mucosal surface. While neutrophils present in the lumen can aid in eradicating offending bacteria via potent killing mechanisms, such mechanisms are non-specific and can lead to host tissue damage if excessive. These killing mechanisms involve PMN release of proteases such as elastase as well as reactive oxygen species, which directly cause damage to mucosal surfaces and contribute to the pathology of the disease. We have recently discovered that enteric pathogen interactions with the host intestinal epithelial cells results in signal transduction cascades, which lead to the production and secretion of the eicosanoid hepoxilin A₃ (HXA₃). This potent PMN chemoattractant directs the final step of neutrophil recruitment across the intestinal epithelium. More recently, we have also revealed that lung epithelial cells produce and secrete HXA₃ in response to Pseudomonas aeruginosa infection and guide neutrophils across airway mucosal surface. Based on these observations, we speculate that this pathway may represent a conserved innate immune mechanism for detection and eradiation of pathogens interfacing with the host mucosal surface. Furthermore, since the epithelium most likely evolved to generate significant levels of HXA₃ to colonization by pathogens, we are exploring the possibility that such signaling pathways could be aberrantly regulated during idiopathic inflammatory diseases such as inflammatory bowel disease, cystic fibrosis, chronic obstructive pulmonary disease, and cirrhosis.

Ongoing Projects

1. Current work from my laboratory is focused on defining the molecular and cellular mechanism(s), which underlie HXA₃ production and neutrophil transepithelial migration in response to infection with the enteric pathogens Salmonella typhimurium and Shigella flexneri, and the lung pathogen, P. aeruginosa. Thus, understanding of this newly identified pathway may lead to more targeted therapies to either relieve excessive inflammation or to enhance a therapeutic inflammatory response.
2. As a corollary to the above study directive, we are targeting the bacterial genes that are responsible for triggering the HXA₃ pathway in both the intestine and airway epithlium.
3. We are beginning translational studies to address the clinical significance of HXA₃ in disease pathologies as secretion of this eicosanoid may provide an important new therapeutic target for treatment of acute and chronic diseases of intestinal, lung and perhaps other mucosal surfaces.

Contact Information

Phone: 617-726-4168
Fax: 617-726-4172
E-mail: mccormic@helix.mgh.harvard.edu