Role of Iron and IscR in the Regulation of Yersinia pseudotuberculosis Pathogenesis

Previous studies suggested that the transcription factor, IscR, positively regulates the main virulence determinant in Yersinia pseudotuberculosis: the type III secretion system (T3SS). IscR in E. coli is an iron-sulfur [2Fe-2S] cluster coordinating global transcriptional regulator that has been shown to bind different DNA target sequences dependent upon [2Fe-2S] coordination. When bound to a [2Fe-2S] cluster, Holo-IscR can bind both a Motif I or Motif II IscR binding site, however, clusterless IscR, or Apo-IscR, can only bind a Motif II site. Given that the Fe-S cluster status of IscR changes in response to environmental signals such as oxygen tension, iron levels, and oxidative stress, we hypothesized that Yersinia pseudotuberculosis senses changes in these signals within the host through IscR to optimize expression of virulence factors. The first part of this work used two mouse models of hereditary hemochromatosis to determine how altered iron environments influence Yersinia pseudotuberculosis pathogenesis and T3SS expression in the host. We and others found that although the T3SS is required to cause disease in healthy mice, it is less critical in mice with hereditary hemochromatosis, suggesting that Yersinia pathogenesis is fundamentally different in these iron overloaded animals. The second goal of my dissertation research was to determine the role of IscR in processes potentially important for virulence in Yersinia pseudotuberculosis and independent of the T3SS. We showed that IscR plays a role in regulation of a heme uptake system in Yersinia pseudotuberculosis and is involved in Yersinia pseudotuberculosis survival in blood. The third and final goal of this work was was to determine the impact of the IscR Motif II site in the promoter of lcrF, the Yersinia T3SS master regulator, on type III secretion and virulence. Our data show that suggest that this site is essential for optimal environmental control of the lcrF promoter by IscR in vivo