Investigation of the effect of C. Difficile toxins on cell migration

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Cell migration is a fundamental process that critically enables many physiological functions including host defense and wound healing, and is important for the pathology of various diseases such as bacterial infection, autoimmune diseases, cancers etc. Particularly, targetting trafficking regulatory signaling molecules expressed on specific leukocyte subsets has led to promising therapeutic approaches for diseases. Similarly, migratory responses to cellular signals are important for epithelial cells to mediate wound healing and the wound repair can be interfered when migration signaling of epithelial cells are inhibited. Interestingly, previous studies showed that Clostridium difficile toxins cause reduced migration of intestinal epithelial cell, but promote neutrophil migration and chemotaxis. The effects of C. difficile toxins on the migration of epithelial cells and immune cells make it a potential target for treating intestinal diseases and other cell trafficking mediated diseases. Therefore, the main goal of this proposed study is to investigate the effect of C. difficile toxins on cell migration and the related mechanisms for guiding the development of therapeutics. This study will integrate the research strength of Dr. Francis Lin's Immunotrafficking lab at the University of Manitoba in cell migration and trafficking with the interest and research capability of Cangene Cooperation in therapeutic products development. In the six months of granting period under this NSERC Engage grant, the team will first characterize the effects of C. difficile toxins on the migration and chemotaxis of intestinal epithelial cells, human neutrophils and T lymphocytes. Next, the team will investigate the underlying cellular mechanisms by examining the effect of the toxins on signaling molecules for gradient sensing and cell migration and on cytoskeleton organization. The outcomes of the proposed study will generate important insight on the regulatory effects of C. difficile toxins on cell migration and will serve as the basis for drug development by Cangene which will benefit Canadians and the world.