The goal of this research program is to develop a mechanistic understanding of the general stress response (GSR) signaling system in the select agent pathogen, Brucella abortus. Our preliminary data demonstrate that this signaling system controls environmental stress adaptation and chronic infection in a mammalian infection model. B. abortus GSR signaling is controlled in part by the PhyR protein, a conserved regulator of adaptation to environmental stress that is broadly conserved in the ?-proteobacterial clade. PhyR contains an amino terminal ECF ?-like domain and a carboxy-terminal TCS receiver domain. Phosphorylation activates PhyR as an anti-anti-? factor and releases the classical ECF ? factor, ?E1 to directly regulate gene expression during stress. Our multi-disciplinary investigation of PhyR, ?E1 and other components of the GSR signaling system will define the mechanistic underpinnings of general stress signaling in a pathogen of significant human health, agricultural, and biodefense import. Moreover, the experiments proposed herein have the potential to inform new treatments for ?-proteobacterial disease such as brucellosis. As mentioned above, this proposal is highly multi-disciplinary, spanning genetics, biochemistry, molecular biophysics, cell biology, and whole-animal infection studies. I will conduct these studies with a team of three experienced postdoctoral fellows, all of whom have expertise working on this BSL3 select agent in containment at the University of Chicago Howard Taylor Ricketts Regional Biocontainment Laboratory.
The specific aims of this project are: 1) Define the role of the sensor histidine kinase, LovhK, as a GSR stress sensor, and characterize the molecular basis of stress signal detection by LovhK. 2) Define signals that activate the B. abortus general stress response in vitro and in a mammalian infection model. 3) Elucidate the structural mechanism of GSR activation.

Public Health Relevance

Bacterial cells must detect and adapt to a broad range of chemical and physical signals in their environment to survive. Understanding the regulatory mechanisms that govern adaptive cellular responses can greatly impact our ability to manipulate and control bacterial growth. This project focuses on characterization of a conserved stress signaling system that controls survival of the pathogenic bacterium, Brucella abortus, inside its mammalian host.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI107159-01A1
Application #
8694631
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Mukhopadhyay, Suman
Project Start
2014-02-01
Project End
2019-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$395,790
Indirect Cost
$145,290
Name
University of Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Kim, Hye-Sook; Willett, Jonathan W; Jain-Gupta, Neeta et al. (2014) The Brucella abortus virulence regulator, LovhK, is a sensor kinase in the general stress response signalling pathway. Mol Microbiol 94:913-25