Enterotoxigenic Escherichia coli (ETEC) are a major cause of diarrheal disease in infants and small children and in travelers to developing countries, including military personnel. The first step in establishment of infection is attachment of the pathogen to the host tissue, which is believed to be mediated by pili (and/or thinner, more flexible fibrillar structures). The major long-term goals of this work are to understand the mechanisms by which pili are synthesized and the mechanisms that regulate their synthesis. A limited number of serologically different pili prevalent among ETEC strains isolated from human disease include a group encoded by homologous genes, for which CS1 serves as the prototype. The investigators found that the genes encoding CS1 are positively regulated by Rns, which shows homology to AraC. The investigators have found that autoactivation by Rns involves DNA regions both upstream and downstream of the regulated promoter.Although this is unprecedented, the investigators found that many Rns-related global regulators of virulence determinants of enteric pathogens can substitute for Rns and therefore act similarly. The investigators wish to study regulation of expression of Rns and of CS1 pili further.
Aim I addresses the regulation of Rns. In other systems activated by a Rns-related protein, more than one virulence operon is usually controlled. Preliminary work indicates that this appears to be the case in ETEC as well.
Aim II proposes to continue this work with the hope of identifying other virulence factors of ETEC and better understanding the pathology of the infections ETEC cause. The investigators have found that the genes needed for synthesis of human ETEC pili are completely unrelated to those of other pili and CS1 pili appear to be much simpler structures, so it seems possible that a detailed understanding of their morphogenesis is within reach.
Aims III and IV of this proposal are directed at approaching this.The investigators hope that this work will suggest new approaches to development of human anti-ETEC vaccines and therapies, as well as providing a greater understanding of protein interaction and assembly of multi-protein structures in bacteria.
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