Pathogenic bacteria are often capable of killing cells within the hosts they infect. Themolecular mechanisms underlying the cytotoxic actions of bacteria on human cells are only partly understood, but generally they involve secretion of killer proteins from bacteria, and often these proteins are injected into host cells by Type III or IV secretion mechanisms. Examples of apoptosis-inducing virulence factors have been found in Yersinia (YopJ), Shigella (ipa), Salmonella (sip), and Anthrax (Lethal Factor) species. The mechanisms by which these bacterial gene products induce apoptosis of human cells are diverse. Knowledge of apoptosis-inducing virulence factors and information about their mechanisms of action can provide the basis for strategies designed to treat or prevent bacterial disease. Using bioinformatics approaches, we have identified several candidate apoptosis-inducing virulence factors encoded in the genomes of pathogenic bacteria. We propose to characterize the apoptosis-inducing activity of these bacterial proteins and to determine their mechanisms of action in human cells. It is hypothesized that some of these bacterial proteins will prove to be virulence factors, which are important for causation of disease. A combination of cellular, molecular, and biochemical methods will be applied to characterize the mechanisms of these candidate virulence factors, with the validated factors then progressing into more in-depth structural analysis through collaborations with other scientists participating in the project. Where warranted, bacterial apoptosis-inducing proteins will become targets for chemical compound library screening, and the resulting chemical entities will be used for further studies of the pathobiology of the target proteins. Altogether, the information derived from these studies may reveal strategies for preventing or ameliorating cell death induced by pathogenic bacteria, thus complementing traditional antibiotics in the prevention and treatment of bacterial diseases and agents of biological warfare.
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