Pathogenic (diarrheagenic) Escherichia coli are an important cause of food-borne disease in the U.S. and developing countries. Most pathogenic E. coli strains, e.g. EPEC and EHEC, cause mucosal inflammation and disease without deep invasion into the intestinal mucosa or systemic spread. Although much progress has been made in understanding the mechanisms by which pathogenic E. coli cause disease (e.g. toxins), relatively little is known about the host defenses against these pathogens. Based on the lack of deep tissue invasion, we hypothesize that host defenses that operate in the intestinal lumen or at the mucosal surface are key for controlling and eradicating infections with most strains of pathogenic E. coil. Our preliminary data strongly support this notion since we found that B cells are absolutely required for clearance of an EPEC strain in a mouse model of infection. The proposed studies will build on this observation and define the mechanisms of B cell-dependent host defense against pathogenic E. coli, using murine infection models. We will focus specifically on the importance of secretory antibodies as immune effectors of B cells. These studies on specific immune effector mechanisms will be complemented with functional investigations on the regulation of mucosal immune defenses against pathogenic E. coli, with a particular focus on the functions of the immunoregulatory cytokine, IL-6. In addition, we will begin to determine the importance of the intestinal epithelium in orchestrating immune defenses against pathogenic E. coli, as epithelial cells are a focal point of interaction between host and most strains of pathogenic E. coll. These experiments will focus particularly on the physiologic functions of the transcription factor, NF-kappaB, in the intestinal epithelium, using a novel murine model we have developed in which a key component of the NF-kB signaling pathway is deleted selectively from intestinal epithelial cells. The proposed studies have the following Specific Aims:
AIM 1. To define the mechanisms of B cell-dependent host defense against pathogenic E. coli.
AIM 2. To determine the functions of IL-6 in host defense against pathogenic E. coli.
AIM 3. To define the importance of epithelial cell NF-kappaB in host defense against pathogenic E. coll. Together, these studies will provide significant new insights into the key host defenses by which the host can eradicate infection with pathogenic E. coli, thus providing an important basis for designing immunization strategies against these pathogens.
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