Enteropathogenic E.coli (EPEC) and enterohaemorrhagic E. coli (EHEC O157:H7) are deadly contaminants in food and water world wide causing diarrhea and death. Formation of actin-filled membrane """"""""pedestals"""""""" (also called """"""""A/E lesions"""""""") beneath EPEC and EHEC are essential for the development of disease. Tyrosine phosphorylation by an unidentified host cell kinase of a translocated bacterial virulence factor, called Tir, is essential for EPEC pedestal formation. Our preliminary evidence indicates (i) that the cellular kinase resembles Abl, but that other tyrosine kinases may also suffice, (ii) that Abl or a related kinase regulates both EPEC and EHEC pathogenesis, and (iii) that PD compounds, which inhibit Abl kinase and are being developed to treat cancer caused by dysregulated Abl, block pathogenic effects in vitro of EPEC and EHEC, and of C. rodentium, a related pathogen that forms A/E lesions in mice. The goal of Aim I is to identify redundant Abl-like kinases. The goal of Aim II is to determine how Abl kinase regulates formation of A/E lesions. Such information will prove essential to understanding the physiological mechanisms of A/E lesion formation, and will inform the design of even more specific inhibitors useful in treating not only bacterial infections but also cancers caused by dysregulated tyrosine kinases. The goal of Aim III is to establish the efficacy of PD inhibitors in mice infected with C. rodentium. Such experiments are an important prelude to clinical testing of drug efficacy in human patients infected with EPEC or EHEC. The need is apparent. EPEC and EHEC are classified by the NIAID as Category B pathogens. In developing countries, antibiotics and rehydration therapy are generally unavailable to treat EPEC infections, and a requirement for high patient compliance further reduces their efficacy when they are available. For EHEC, antibiotics exacerbate symptoms perhaps by lysing bacteria and releasing toxins and, in the United States, are contraindicated. Furthermore, drug-resistant EHEC strains have been documented. In this regard, because PD compounds affect the host and not the bacterium, selecting resistant strains with PD is far less likely than with conventional antibiotics or antimicrobial compounds. ? ?
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