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.

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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Mukhopadhyay, Suman
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University of Chicago
Schools of Medicine
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Luebke, Justin L; Eaton, Daniel S; Sachleben, Joseph R et al. (2018) Allosteric control of a bacterial stress response system by an anti-? factor. Mol Microbiol 107:164-179
Herrou, Julien; Willett, Jonathan W; Fiebig, Aretha et al. (2018) Periplasmic protein EipA determines envelope stress resistance and virulence in Brucella abortus. Mol Microbiol :
Herrou, Julien; Czy?, Daniel M; Fiebig, Aretha et al. (2018) Molecular control of gene expression by Brucella BaaR, an IclR-type transcriptional repressor. J Biol Chem 293:7437-7456
Czy?, Daniel M; Willett, Jonathan W; Crosson, Sean (2017) Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen. J Bacteriol 199:
Herrou, Julien; Willett, Jonathan W; Czy?, Daniel M et al. (2017) Conserved ABC Transport System Regulated by the General Stress Response Pathways of Alpha- and Gammaproteobacteria. J Bacteriol 199:
Herrou, Julien; Crosson, Sean; Fiebig, Aretha (2017) Structure and function of HWE/HisKA2-family sensor histidine kinases. Curr Opin Microbiol 36:47-54
Willett, Jonathan W; Crosson, Sean (2017) Atypical modes of bacterial histidine kinase signaling. Mol Microbiol 103:197-202
Czy?, Daniel M; Jain-Gupta, Neeta; Shuman, Howard A et al. (2016) A dual-targeting approach to inhibit Brucella abortus replication in human cells. Sci Rep 6:35835
Willett, Jonathan W; Herrou, Julien; Czyz, Daniel M et al. (2016) Brucella abortus ?rpoE1 confers protective immunity against wild type challenge in a mouse model of brucellosis. Vaccine 34:5073-5081
Herrou, Julien; Czy?, Daniel M; Willett, Jonathan W et al. (2016) WrpA Is an Atypical Flavodoxin Family Protein under Regulatory Control of the Brucella abortus General Stress Response System. J Bacteriol 198:1281-93

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