INTESTINAL IMMUNE SYSTEM--HOST ENVIRONMENT INTERACTIONS

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The overall goal of the Program Project is to characterize mechanisms that govern host inflammatory and immune responses at mucosal surfaces in the gastrointestinal tract. The six projects explore strategies used by the host in interacting with invasive and noninvasive bacterial and protozoan enteric pathogens, and strategies used by the pathogens in their interactions with the host's intestinal mucosa. Salmonella and E. histolytica are used as models of enteroinvasive pathogens, and Cryptosporidium parvum is used as a model of minimally invasive pathogen that resides exclusively in the intestinal epithelium. In contrast, G. lamblia infection in the small intestine is used as a model of noninvasive pathogen that can result in significant mucosal disease. The Program draws on strengths inherent in in vitro and in vivo models of intestinal mucosal infection to accomplish its objectives. The Program brings together investigators with expertise in immunology, molecular biology, microbiology and physiology. Research Unit 1 consists of two projects: Project 1 studies the host mucosal response to noninvasive intraluminal pathogens and minimally invasive enteric pathogens that reside in epithelial cells, focusing on the importance of PGHS2/prostaglandins, NOS2/NO and defensins as part of the host's responses to those pathogens. Project 2 focuses on intestinal epithelial cell responses to invasive bacterial pathogens, defines pathways that can be used to manipulate host epithelial pro-inflammatory responses in vivo. Research Unit 2 examines the role physiologic stimuli from intestinal epithelial cells play in modulating the growth and differentiation of the intraluminal protozoan parasite G. lamblia and its ability to colonize the intestine. Research Unit 3 examines host factors important for resistance to Salmonella and virulence strategies used by pathogenic Salmonella to invade and replicate in the intestinal mucosa. Research Unit 4 characterizes the strategies used by E. histolytica to invade its human host and host protective responses to E. histolytica infection. Research Unit 5 explores mechanisms by which fluid and electrolyte transport at mucosal surfaces can be altered by invasive and luminal microbes. The projects are supported by four Cores: a Cell Culture and Assay Core, a Histopathology Core, a Mouse Breeding/Intestinal Xenograft Core, and an Administrative Core.