Host iron and Yersinia pathogenesis

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The majority of bacterial pathogens require iron as an essential nutrient and mammalian hosts have evolved a number of mechanisms to sequester iron and limit the growth of invading microbes. However, bacteria have, in turn, evolved a myriad of iron uptake strategies as well as regulatory proteins that sense iron levels to control expression of iron acquisition systems and other genes critical for virulence. Iron is an important factor in the pathogenesis of the plague agent Yersinia pestis and the enteropathogens Y. enterocolitica and Y. pseudotuberculosis. We recently showed that Y. pseudotuberculosis uses an iron-sulfur cluster coordinating transcription factor called IscR to drive expression of its major virulence factor, the Ysc type III secretion system (T3SS), and that IscR is required for proper expression of a number of other metabolic and virulence genes. Our preliminary data show that IscR is required for Y. pseudotuberculosis virulence and for survival in blood. As IscR is a global transcriptional regulator, it is critical to determine precisely which IscR-regulated pathways are important for pathogen growth and survival in vivo. To address this, in Aim 1, we will determine the IscR regulon in Y. pseudotuberculosis, how it is influenced by iron levels, and assess its conservation in Y. pestis and Y. enterocolitica. In addition, in Aim 2, we will test how IscR control of the Ysc T3SS impacts Y. pseudotuberculosis virulence in normal and iron overloaded mice. Lastly, in Aim 3, we will determine how IscR enables Y. pseudotuberculosis survival in blood and how this influences disseminated infection. At the conclusion of this study, we will have established the pathways controlled by IscR in Yersinia and determined how they contribute to pathogenesis. This work will help to elucidate the ways in which pathogens sense their environment to optimize virulence factor utilization during infection.