Urinary tract infections (UTIs) are among the most frequent bacterial infections afflicting humans and have a high degree of recurrence. With rising resistance to front-line antibiotics, there is a pressing need for the development of targeted strategies aimed at preventing and/or treating UTIs. Uropathogenic Escherichia coli (UPEC) account for the majority of UTIs and can form robust extracellular biofilms, as well as biofilm- like intracellular bacterial communities (IBCs). Among the factors impacting IBC formation is the QseC sensor kinase, the disruption of which diminishes IBC formation and attenuates UPEC virulence. We have shown that QseC is required for the de-phosphorylation and deactivation of its cognate response regulator QseB, which becomes constitutively activated in the absence of QseC. Constitutively active QseB leads to the dysregulation of >500 genes, interferes with core metabolic processes and downregulates virulence gene expression. Investigating the source of QseB phosphorylation in the absence of QseC identified the PmrAB two-component system (TCS) as the primary QseB activator. We went on to show that in wild-type UPEC, signal reception by PmrB can also activate the non-cognate partner QseB, indicating a potential overlap between QseBC and PmrAB signaling. These results lead to two hypotheses: 1) There is robust cross-talk between non-cognate TCS partners that is of physiological significance during UPEC pathogenesis and, 2) We can target QseC function as a means to attenuate virulence. This proposal will engage fundamental questions about the regulatory interactions between QseBC and PmrAB and their role in UTI pathogenesis, and endeavor to harness this information to treat/prevent UTIs.
Aims 1 and 2 will elucidate the molecular mechanisms underlying the cross-talk between UPEC QseBC and PmrAB.
Aim 3 will probe the role of QseBC-PmrAB interactions during infection and will identify compounds that target the QseC phosphatase function, and/or bias cross-talk between QseB and PmrB. We have developed an extensive array of molecular tools that we are using in our studies, including non-polar deletion mutants, as well as inactive or constitutively active point mutants. Combined with the well-established murine model of UTI we are using, our microscopy capabilities to track infection in the bladder, and the impressive facilities and resources of Vanderbilt University, we are confident that we will harness information that will elucidate the QseBC-PmrAB molecular interplay within and outside the host. Our long-term goal is to leverage the outcomes of the herein proposed studies to develop better therapies against UPEC infection.

Public Health Relevance

Urinary tract infections, caused primarily by the bacteria uropathogenic E. coli (UPEC), afflict millions world- wide, causing considerable disease complications due to their high frequency and degree of recurrence. Current treatments against UTIs are becoming less effective due to the rising resistance of bacteria to antibiotics, making it very important to develop new strategies for eliminating bacteria from the urinary tract. This research is aimed at a) understanding how two regulatory systems in UPEC interface to allow bacteria to adapt to different environments and establish disease and b) leveraging the obtained information towards manipulating these system interactions as a therapeutic approach against UPEC infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Ernst, Nancy L
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Vanderbilt University Medical Center
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Steiner, Bradley D; Eberly, Allison R; Hurst, Melanie N et al. (2018) Evidence of Cross-Regulation in Two Closely Related Pyruvate-Sensing Systems in Uropathogenic Escherichia coli. J Membr Biol 251:65-74
Breland, Erin J; Eberly, Allison R; Hadjifrangiskou, Maria (2017) An Overview of Two-Component Signal Transduction Systems Implicated in Extra-Intestinal Pathogenic E. coli Infections. Front Cell Infect Microbiol 7:162
Behr, Stefan; Kristoficova, Ivica; Witting, Michael et al. (2017) Identification of a High-Affinity Pyruvate Receptor in Escherichia coli. Sci Rep 7:1388
Guckes, Kirsten R; Breland, Erin J; Zhang, Ellisa W et al. (2017) Signaling by two-component system noncognate partners promotes intrinsic tolerance to polymyxin B in uropathogenic Escherichia coli. Sci Signal 10:
Breland, Erin J; Zhang, Ellisa W; Bermudez, Tomas et al. (2017) The Histidine Residue of QseC Is Required for Canonical Signaling between QseB and PmrB in Uropathogenic Escherichia coli. J Bacteriol 199: