The research described in this proposal will use a novel reversible intestinal infection model developed in my laboratory (Hapfelmeier et al., 2010. Science 328:1705-1709) for the detailed study of the differences between intestinal commensal and pathogen induced immunity. In my earlier work this system allowed fully reversible intestinal exposure of germ-free animals with live bacteria so that the commensal-induced immunity could be uncoupled from persistent bacterial colonization. This permitted detailed quantitative and temporal analysis of host responses to encounter of live commensal bacteria. In the presented research project the reversible bacterial colonization model will be extended to produce a model of reversible intestinal infection with intestinal pathogenic bacteria to uncouple pathogen immunity from pathogen immune evasion.Most microbes we encounter are commensal bacteria that benignly colonize the intestinal lumen. The immune system is well adapted for commensal mutualism, and mutualism breakdown, as in inflammatory bowel disease, is relatively rare. In contrast, pathogenic bacterial encounters less frequent and countered with anti-pathogen immune defense and inflammation. During infection, the host-pathogen relationship is a competition between anti-bacterial immunity and pathogen immune evasion – the latter is well-studied, the former largely in systems where the pathogen proliferates and immune evasion overlays immunity. There is the need to experimentally uncouple pathogen immunity and pathogen immune evasion. Our novel approach permits a detailed comparative analysis of pathogen and commensal immune induction and will shed new light on the mechanisms of pathogen versus commensal immune recognition. This knowledge is critical for the design of efficient bacterial vaccines and the understanding of the abnormal immune responses directed against commensal microbes in chronic inflammatory diseases.