Regulation of Innate Immunity to Enteric Infection

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Enteric infections are a major cause of morbidity and death worldwide. The overall goal of Unit 1 is to define key mechanisms that regulate host innate immune defense to enteric infection in the colon and small intestine. Dendritic cells (DC) and intestinal epithelial cells are important mucosal sentinels that initiate immunity to enteric pathogens. We will use two model enteric pathogens to probe DC and DC-epithelial cell communication in the colon and small intestine in vivo. C. rodentium infection, a murine attaching and effacing (A/E) lesion-inducing pathogen, which resembles EPEC and EHEC infection in humans, will be used to probe colonic mucosal responses, and rotavirus, a clinically important viral pathogen will be used to probe small intestinal responses. In preliminary studies, we show that the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) has important non redundant activity in vivo in influencing DC and DC- epithelial cell communication, and governs the character and outcome of the host response to infection with C. rodentium. This led to our hypothesis that GM-CSF has novel activities on DC and epithelial cells in the infected intestinal mucosa that go beyond its previously recognized functions, and determine the outcome of enteric infection. Therefore, an overarching, but not exclusive, goal of the proposed studies includes defining mechanisms by which GM-CSF governs DC and epithelial cell innate responses to enteric pathogens. We will use gene targeted mouse models with in vivo and ex-vivo approaches to address three Specific Aims. Aim 1 will determine mechanisms by which GM-CSF mediates host innate protection to a model A/E pathogen in vivo. Aim 2 will characterize the pathways by which GM-CSF activates production of CCL22, an epithelial cell-produced mediator that is important for GM-CSF-induced DC recruitment and mucosal localization. Aim 3 will determine mechanisms by which DC, epithelial cells and GM-CSF orchestrate host innate immunity and mucosal protection to small intestinal infection in vivo. We will benefit immensely from our collaborations and close interactions with Drs. Eckmann, Raz and Cheroutre by combining our model systems for studies downstream of DC activation, which define mechanisms that link innate and acquired immunity. Our studies require extensive use of the Mouse Model Core, the Histopathology Core (Core B) for tissue processing and immunohistochemistry, and the Imaging and Cell Sorting Core (Core C) for state of the art studies using confocal spectral deconvolution microscopy and live imaging 2-photon microscopy. RELEVANCE (See instructions): Intestinal infections result in extensive morbidity and millions of deaths worldwide each year. Among enteric infections, human A/E pathogens [EPEC and EHEC (the "hamburger bacillus")] and Rotavirus (-800,000 deaths per year) rank among the most frequent causes of dian'heal illness and death. We will determine how the host's innate immune system helps to defend against those infections. We anticipate new infonnation obtained will lead to important and novel approaches for preventing and treating intestinal infections and new insights into the causation of post infectious inflammatory diseases in the intestinal tract.