Vibrio cholerae, a major human pathogen responsible for both endemic and epidemic cholera, has an absolute requirement for iron. Because V. cholerae must be able to obtain iron in a variety of different environments in and outside of host organisms, it has evolved multiple iron acquisition systems and can use iron from a variety of sources. These iron transport systems include the endogenous siderophore vibriobactin, receptors for exogenous siderophores and for heme, and ferric and ferrous iron uptake systems. Iron transport systems are tightly regulated to avoid either iron starvation or iron toxicity, and there is both transcriptional and post-transcriptional regulation of iron transport and iron metabolism. Regulation is mediated by iron and the global regulator Fur and by the small RNA RyhB. There is evidence for additional levels of regulation. We will characterize the V. cholerae iron transport systems, the regulation of their expression, and their role in survival of V. cholerae in the environment and in the host. These systems will be characterized using molecular biology, genetics, and biochemical techniques. As we complete the characterization of all the iron transport systems that this pathogen uses, we can determine their roles in pathogenesis and further dissect the complex regulatory network by which environmental signals regulate the expression V. cholerae iron transport genes.
The specific aims of this grant are: 1) Identify the complete complement of V. cholerae iron transport systems. 2) Characterize the ferrous iron transporter Feo and the novel VciB iron acquisition system. These systems are of particular interest since they are both expressed by bacteria during infection of the host and are likely to be major iron uptake systems in the microaerobic environment of the intestine. 3) Determine the mechanism of regulation of V. cholerae iron transport genes in response to environmental signals. The systems respond to multiple, different signals to optimize iron acquisition and growth of V. cholerae in the variety of environments in which it is found, and we propose to define these regulatory networks. It is important to understand bacterial iron transport systems and their regulation, because the ability of pathogens to compete with their host for this essential element is a critical component of the host-pathogen interaction. Defining and characterizing the V. cholerae iron transport systems at the molecular level and understanding their expression in response to different environmental conditions will provide the basis for developing strategies to control this major human pathogen. The results of these studies are likely to be broadly applicable to human pathogenic bacteria, since the majority of them must acquire iron during infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
3R56AI050669-06A2S1
Application #
7834648
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Hall, Robert H
Project Start
2009-06-01
Project End
2010-11-30
Budget Start
2009-06-01
Budget End
2010-11-30
Support Year
6
Fiscal Year
2009
Total Cost
$370,999
Indirect Cost
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Mey, Alexandra R; Butz, Heidi A; Payne, Shelley M (2015) Vibrio cholerae CsrA Regulates ToxR Levels in Response to Amino Acids and Is Essential for Virulence. MBio 6:e01064
Weaver, Emily A; Wyckoff, Elizabeth E; Mey, Alexandra R et al. (2013) FeoA and FeoC are essential components of the Vibrio cholerae ferrous iron uptake system, and FeoC interacts with FeoB. J Bacteriol 195:4826-35
Mey, Alexandra R; Craig, Stephanie A; Payne, Shelley M (2012) Effects of amino acid supplementation on porin expression and ToxR levels in Vibrio cholerae. Infect Immun 80:518-28
Craig, S A; Carpenter, C D; Mey, A R et al. (2011) Positive regulation of the Vibrio cholerae porin OmpT by iron and fur. J Bacteriol 193:6505-11
Wyckoff, Elizabeth E; Payne, Shelley M (2011) The Vibrio cholerae VctPDGC system transports catechol siderophores and a siderophore-free iron ligand. Mol Microbiol 81:1446-58
Be'er, Avraham; Ariel, Gil; Kalisman, Oren et al. (2010) Lethal protein produced in response to competition between sibling bacterial colonies. Proc Natl Acad Sci U S A 107:6258-63
Roux, Agnès; Payne, Shelley M; Gilmore, Michael S (2009) Microbial telesensing: probing the environment for friends, foes, and food. Cell Host Microbe 6:115-24