Complement activation of intestinal epithelial cells

The boundary between your tissues and the lumen in your intestines is a thin sheet of cells called epithelial cells. From this interface with the environment epithelial cells must balance being tolerant of food and some bacteria yet respond with inflammation to other pathogenic bacteria. We think that one way the epithelial cells know to respond to pathogenic bacteria is because another natural defence system becomes activated directly by the bacteria. This defence system is called complement and is intended to make bacteria more easily killed by white blood cells and directly kills bacteria by forming pores on their surface. Complement activation requires a number of proteins be split. We have discovered that epithelial cells have the receptors for these split complement proteins but we do not know what happens to the cells as a result of binding the split proteins. This grant will explore the idea that the split complement proteins cause the epithelial cells to initiate inflammation. This includes recruiting white blood cells from the blood into the gut tissues. Epithelial cells have other molecules on their surface to protect them from the pores that complement assembles. We expect that binding the split complement proteins will result in epithelial cells making more of these protective molecules, to minimize damage by complement on the gut itself. These ideas will be tested using epithelial cells in petri dishes but our findings will then be validated in mice. Mice are chosen because they can be made deficient in complement proteins. The significance is that failures in the communication between epithelial cells and complement may compromise the host response to pathogenic bacteria, possibly causing or worsening disease in man and animals.