DESCRIPTION (provided by applicant): The enterotoxigenic Escherichia coli (ETEC) are a genetically diverse type of pathogenic E. coli that cause astounding numbers of cases of diarrheal illness worldwide, and have emerged as a cause of large-scale outbreaks of diarrhea in the United States. These organisms share the ability to produce, secrete, and deliver heat-stable (ST) and/or heat-liable (LT) toxins to the intestinal lining cells ultimately causing diarrhea, which can be severe and cholera-like. The toxin genes encoded on plasmids, were identified shortly after the discovery of these toxin-producing E. coli more than 40 years ago. Most research on ETEC until very recently focused on a small number of molecules, namely the toxins themselves and plasmid-encoded fingerlike colonization factors (CFs). Unfortunately, vaccine development centered on these antigens alone has proven to be very challenging in part because of the heterogeneity of the CF molecules and the fact that the toxins do not appear to afford complete protection against disease (in the case of LT), or are not immunogenic (as is the case for ST). The recent failure of several vaccines incorporating these antigens has prompted both a search for alternative strategiesand a return to basic pathogenesis studies in order to address gaps in our understanding of how these globally important pathogens cause disease. While much is known about the molecular action of these toxins once they enter host cells, very little is known about how the bacteria effectively deliver these toxins to their respective cell surface receptors. These studies will use recently developed molecular tools, capitalize on recent discoveries of new agents, and exploit the state-of-the-art methodology to define the roll of novel molecules on the surface of ETEC that promote the effective delivery of these toxins. The long-term goal of these studies is to translate this information into rational design of a safe, effective, and broadly protective ETEC vaccine.

PUBLIC HEALTH RELEVANCE: Diarrheal illness caused by enterotoxigenic Escherichia coli (ETEC) is truly a global health problem with nearly a billion estimated annual cases worldwide. These organisms remain the number one cause of diarrhea in travelers, and in soldiers deployed to areas where enteric infections are hyper-endemic. ETEC has increasingly been indentified as a cause of illness in the United States having caused multiple recent large-scale food-borne outbreaks. This project focuses on a number of highly conserved molecules operative in ETEC and other enteric pathogens as well as a diverse group of pathonogenic bacteria (including E. coli that cause urinary tract infections, and Pseudomonas) that share very similar virulence factors, and which are also of significant importance to the health of Veterans.