Virulence role and regulation of Shigella suf genes

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DESCRIPTION (provided by applicant): Shigella species are the causative agents of shigellosis, which results in approximately 600,000 deaths per year. Transmission usually occurs via contaminated food or water, or through person-to-person contact. Basic research aimed at characterizing the genes that Shigella uses to adapt to the human host will be useful in designing effective therapies and vaccines. Furthermore, since Shigella virulence depends largely on its ability to live inside human colon cells, a complete understanding of the mechanisms that Shigella uses to survive and multiply in the intracellular environment will provide better insight into the lifestyles of intracellular pathogens. The long-term research goal is to elucidate the metabolic and physiological processes that Shigella employs to survive and multiply the eukaryotic cell. An approach to accomplishing this goal was to characterize Shigella genes that are induced when Shigella is in the eukaryotic cytoplasm. One particular locus (suf) that is induced in response to the eukaryotic intracellular environment is homologous to a locus that enhances virulence and oxidative stress survival in the plant pathogen Erwinia chrysanthemi. Three of the six suf genes are predicted to mediate iron-sulfur cluster synthesis. This led to the hypothesis that the Shigella suf genes mediate adaptation to the eukaryotic cytoplasm, possibly through enhanced iron-sulfur cluster metabolism and/or oxidative stress survival. The goal of this project is to characterize the S. flexneri suf locus, specifically the regulation of the suf genes and the contribution of the Suf system to Shigella adaptation to the eukaryotic cytoplasm. Specific aim 1 is to identify the elements that regulate suf expression in vitro and in vivo. Because the sufA gene is induced when Shigella is in the eukaryotic cytoplasm, specific aim 2 is to assess whether the Shigella Suf proteins are required for survival and/or multiplication in the eukaryotic intracellular environment. Characterization of the Shigella suf genes will provide information about the importance of the suf genes when Shigella is in the intracellular environment and will provide a better understanding of how Shigella senses and adapts to the eukaryotic intracellular environment.