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Research
Current Projects by Principal Investigator
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Research
Beth McCormick, PhD
Associate Professor of Pediatrics 
Phone: 617-726-4168
Fax: 617-726-4172
Email: mccormic@helix.mgh.harvard.edu
Curriculum Vita
Fellows: Bryan Hurley, Karen Mumy, Dario Siccardi, Daniel Wall
My research is focused on the molecular 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. My original interest in this field of research lead to the development of a novel model system to examine the immunopathology of intestinal inflammation in vitro. My findings from these studies were the first to demonstrate that a pro-inflammatory program, which could recruit inflammatory cells (neutrophils), was orchestrated by epithelial cells in response to enteric pathogens. This work led to the identification of distinct chemokines released from intestinal epithelial cells, which work in concert to direct neutrophil movement into the intestinal lumen in response to enteric pathogens. Research projects in my laboratory are now directed at unraveling the molecular nature of these signals.
The Salmonella project is an extension of my previous work, which demonstrated that intestinal epithelial cells respond to lumenal pathogens, such as S. typhimurium, by releasing distinctive proinflammatory chemoattractants, which sequentially orchestrate PMN movement across the intestinal epithelium. I have found that S. typhimurium-intestinal epithelial cell interactions induce the epithelial synthesis and polarized basolateral release of the potent PMN chemokine, interleukin-8 (IL-8). Such basolateral release of IL-8 imprints subepithelial matrices with long-lived haptotactic gradients that function to guide PMN through the lamina propria to a subepithelial position. However, basolateral release of this chemokine is insufficient to induce migration of PMN across the intestinal epithelium, suggesting that the production of other inflammatory mediator(s), whose release would be polarized apically, are important for the execution of this step in the inflammatory pathway. Recently, we have identified the first such proinflammatory mediator called pathogen elicited epithelial chemoattractant (PEEC), which we have recently identified as the eicosanoid hepoxilin A3. Thus, the general goal of the RO1 funded project is to sort out the molecular and cellular mechanisms by which S. typhimurium induces the epithelial secretion of hepoxilin A3.
The Shigella project is focused on how Shigella flexneri is able to coordinate the mucosal immune response, which leads to an intense inflammatory reaction in humans characterized by bacillary dysentery. The research goals proposed are directed at (i) understanding the nature of the species dependency of Shigella with the human intestine, and (ii) elucidating the molecular basis by which Shigella foster acute infectious colitis. Our studies employ a patho-evolutionary approach and have lead to novel observations with regard to S. flexneri induced-inflammation. These observations support the concept that Shigella evolved from non-pathogenic ancestors by the loss of genes that are incompatible with virulence. Research in my is now directed at exploiting these genes as a molecular tool to unlock the molecular mechanism by which Shigella induces an intense inflammatory response.
The newest project in my lab, focuses on bacterial infections of the lung, another mucosal surface. Lung disease as a consequence of bacterial infection in many situations is marked by severe inflammation, particularly the accumulation of large numbers of neutrophils in the lumenal space along the respiratory tract. It is currently unclear what bacterial factors can trigger this response and exactly how the neutrophils are directed to the site of infection. Understanding this process is the broad long-term objective of our work.
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