Molecular Pathogenesis of enterotoxigenic E. coli associated enteropathy

Project Summary/Abstract This work focuses on enterotoxigenic Escherichia coli (ETEC), globally the most common bacterial cause of serious diarrheal illness. Originally identified more than 50 years ago as a cause of severe diarrheal illness in patients with clinical presentations indistinguishable from cholera, ETEC continue to threaten the lives of many children in poor regions of the world where sanitation and clean water remain limited. While deaths from diarrheal illness in low-middle income countries have declined, largely due to deployment of oral rehydration therapy, the tremendous morbidity associated with these illnesses remains completely unchecked. ETEC are closely linked to a condition known as environmental enteropathy or environmental enteric dysfunction (EED) that is complicated by sequelae of malnutrition, stunted growth, and intellectual impairment, robbing poor countries of badly needed human capital. Children with malnutrition are also at tremendously increased risk of dying from infectious diarrhea, pneumonia, and other common infections. In addition, ETEC have been linked to a centuries-old enigmatic disease, known as tropical sprue, that is typically diagnosed in adults with substantial repeated exposure to these pathogens. With EED it shares features of poor nutrient absorption, wasting, and alterations of small intestinal morphology. Much is known about of the molecular pathogenesis of acute diarrheal disease, with heat- labile (LT) and heat- stable (ST) toxins signaling through cAMP and cGMP second messenger pathways, respectively, to alter enterocyte ion channels that promote the net efflux of salt and water into the intestinal lumen. However, the biology underlying enteropathic changes to the small intestine and related sequelae are very poorly understood. Our recent studies indicate that ETEC toxins compromise cellular messages critical to the maintenance, biogenesis and function of small intestinal surfaces responsible for nutrient absorption. The current project will therefore address the following questions: · "What is the impact of ETEC and its individual toxins on the absorptive architecture of small intestine?" · "How does repeated ETEC infection affect the overall expression of genes that direct formation of surfaces needed for nutrient absorption?" · "Can we mitigate these effects by toxin-neutralizing vaccination?" Addressing these fundamental questions will fill important gaps in our understanding of the sequelae to ETEC infections, elucidate important features of the molecular pathogenesis of disease, and inform strategies to prevent illnesses that threaten millions of disadvantaged children worldwide.