Yersinia pestis causes a zoonotic disease, plague, with well established reservoirs on every inhabited continent except Australia. Although humans are an accidental, dead-end host, bubonic and pneumonic plague has caused widespread loss of human life during recurrent pandemics. Nearly 2,000 human plague cases occur yearly and outbreaks in Africa, South America and Southeast Asia are common. In addition, Y. pestis is a category A select agent with potential use for bioterrorism. The ability of pathogens to acquire iron from their hosts is a critical requirement for the development of nearly all infectious disease processes. Y. pestis encodes a large number of proven or putative iron transport systems but the siderophore- dependent yersiniabactin (Ybt) and Yfe systems are the most important for causing bubonic plague. In a mouse model of bubonic plague, the Ybt system is essential in the early phases of disease while the Yfe system plays an important role in the later stages of plague. Mutations in ybt but not yfe affect the pathogenesis of pneumonic plague. Our studies indicate that Yfe and Feo (a ferrous iron transporter) play somewhat redundant roles in iron uptake - mutants lacking both systems show more severe phenotypes for in vitro growth, intracellular growth, and pathogenesis in bubonic and pneumonic plague. All these genes are regulated by Fur and iron availability. In addition, the Ybt system is activated by the AraC-type regulator YbtA and the Ybt siderophore. The ultimate goals of my laboratory are to 1) genetically and biochemically characterize the iron transport systems of Y. pestis;2) determine the mechanisms regulating expression of these systems;3) assess the relative importance of these systems in bubonic and pneumonic plague;and 4) explore the potential for new antimicrobial therapies and vaccine components based on these transport systems. In this proposal we will focus on the Ybt system.
The specific aims of this proposal are to 1) characterize Ybt regulation, 2) investigate Ybt transport and iron utilization, and 3) examine Ybt roles in bubonic and pneumonic plague pathogenesis.

Public Health Relevance

Most bacterial pathogens require iron in order to grow and cause disease. Yersinia pestis, the causative agent of plague, produces a small molecule called a siderophore that can remove the iron that it needs from host iron-binding compounds and plays a very important role in both bubonic and pneumonic plague. Understanding how the bacterium makes this siderophore and how its production is regulated may eventually lead to the development of either a vaccine or new drugs against plague and other bacterial diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033481-19
Application #
8389560
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Mukhopadhyay, Suman
Project Start
1993-07-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
19
Fiscal Year
2013
Total Cost
$337,425
Indirect Cost
$107,101
Name
University of Kentucky
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Perry, Robert D; Bobrov, Alexander G; Fetherston, Jacqueline D (2015) The role of transition metal transporters for iron, zinc, manganese, and copper in the pathogenesis of Yersinia pestis. Metallomics 7:965-78
Bobrov, Alexander G; Kirillina, Olga; Fetherston, Jacqueline D et al. (2014) The Yersinia pestis siderophore, yersiniabactin, and the ZnuABC system both contribute to zinc acquisition and the development of lethal septicaemic plague in mice. Mol Microbiol 93:759-75
Perry, Robert D; Craig, Susannah K; Abney, Jennifer et al. (2012) Manganese transporters Yfe and MntH are Fur-regulated and important for the virulence of Yersinia pestis. Microbiology 158:804-15
Perry, Robert D; Bobrov, Alexander G; Kirillina, Olga et al. (2012) Yersinia pestis transition metal divalent cation transporters. Adv Exp Med Biol 954:267-79
Fetherston, Jacqueline D; Mier Jr, Ildefonso; Truszczynska, Helena et al. (2012) The Yfe and Feo transporters are involved in microaerobic growth and virulence of Yersinia pestis in bubonic plague. Infect Immun 80:3880-91
Perry, Robert D; Fetherston, Jacqueline D (2011) Yersiniabactin iron uptake: mechanisms and role in Yersinia pestis pathogenesis. Microbes Infect 13:808-17
Fetherston, Jacqueline D; Kirillina, Olga; Bobrov, Alexander G et al. (2010) The yersiniabactin transport system is critical for the pathogenesis of bubonic and pneumonic plague. Infect Immun 78:2045-52
Miller, M Clarke; Fetherston, Jacqueline D; Pickett, Carol L et al. (2010) Reduced synthesis of the Ybt siderophore or production of aberrant Ybt-like molecules activates transcription of yersiniabactin genes in Yersinia pestis. Microbiology 156:2226-38
Desrosiers, Daniel C; Bearden, Scott W; Mier Jr, Ildefonso et al. (2010) Znu is the predominant zinc importer in Yersinia pestis during in vitro growth but is not essential for virulence. Infect Immun 78:5163-77
Perry, Robert D; Mier Jr, Ildefonso; Fetherston, Jacqueline D (2007) Roles of the Yfe and Feo transporters of Yersinia pestis in iron uptake and intracellular growth. Biometals 20:699-703

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