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.

Public Health Relevance

Iron disorders impact over 30% of the world's population, as iron is an essential nutrient, yet can also be toxic. Most bacterial pathogens require iron for growth and are locked in a battle with their hosts over acquisition of this metal. This project addresses how iron impacts the ability of human pathogenic Yersinia to cause disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacterial Pathogenesis Study Section (BACP)
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Alexander, William A
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University of California Santa Cruz
Public Health & Prev Medicine
Schools of Arts and Sciences
Santa Cruz
United States
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Schwiesow, Leah; Mettert, Erin; Wei, Yahan et al. (2018) Control of hmu Heme Uptake Genes in Yersinia pseudotuberculosis in Response to Iron Sources. Front Cell Infect Microbiol 8:47
Miller, Halie K; Schwiesow, Leah; Au-Yeung, Winnie et al. (2016) Hereditary Hemochromatosis Predisposes Mice to Yersinia pseudotuberculosis Infection Even in the Absence of the Type III Secretion System. Front Cell Infect Microbiol 6:69