Mucosal Immune Barrier in Infection and Inflammation

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DESCRIPTION (provided by applicant): Exposed mucosal surfaces, such as the respiratory, gastrointestinal, and genitourinary surfaces, are lined primarily by a single layer of epithelial cells. This cell layer serves at least two primary functions in the mucosal immune system. First, it is a barrier to the entry of the >95% of infectious agents that enter through mucosal surfaces, as well as a barrier to allergens and other noxious agents. Mucosal infectious diseases include such high priority agents as AIDS and other sexually transmitted diseases, numerous opportunistic infections and emerging and re-emerging diseases, and bio-terrorist agents. Second, in response to these pathologic agents, inflammatory and immune cells are recruited and cross the epithelial barrier, following a chemotactic gradient. This Program Project presents a multidisciplinary and highly interactive approach to these problems. The Project and Core leaders combine a great deal of experience and diverse insights and techniques. Our experimental systems range from in vitro cell culture to genetically modified whole animals, though we focus on lung epithelium as an exemplary mucosal, and Pseudomonas aeruginosa as an exemplary mucosal pathogen. The integrity of the epithelial monolayer is essential to its mucosal immune function. The epithelial monolayer has sophisticated wound-healing mechanisms to maintain its integrity. Project 1 concentrates on the basic mechanisms of epithelial wound healing. Project 2 focuses on how wound healing is altered by P. aeruginosa and closely parallels Project 1. Projects 3 and 4 focus on the movement of inflammatory cells across the epithelial monolayer into the lumen. Project 3 considers the transmigration of the polymorphonuclear neutrophil, specifically the role of CD47 and the ligand for Mac-l. Project 4 focuses on the role of matrix metalloproteases (MMPs) in chemotaxis of inflammatory cells into the lumen. All four projects are supported by all three cores. Core A is administrative. Core B, Cell Isolation and Culture, provides primary lung epithelial cells for all projects. Core C provides Live Cell Multiphoton and Confocal Imaging, which will be vital to all projects. There is very extensive interaction and collaboration through out. For instance, Projects 1, 2 and 4 all utilize mice knocked-out for certain MMPs.