Hypochlorous acid (HOCl), the active component of household bleach, functions as a powerful antimicrobial during the innate immune response. Despite its widespread use, surprisingly little is known about how bacteria sense and respond to bleach. To our knowledge, no HOCl-sensitive transcriptional regulator has been identified in any organism to date. Preliminary results from our lab implicate the conserved NemR protein as an HOCl-specific transcriptional repressor in E. coli. We have evidence that oxidation by HOCl causes the formation of specific intermolecular disulfide bonds in NemR, which modulate transcriptional activity and induce the expression of genes required for bleach tolerance. I will use both in vitro biochemical approaches and in vivo genetic techniques to examine the role that NemR plays in bacterial bleach resistance. I will investigate the mechanism of HOCl sensing by analyzing the role of conserved cysteine residues in NemR and the structural and functional changes in NemR that occur upon HOCl-treatment. The results of this study will have potentially broad implications on our understanding of how cells sense HOCl and repair cellular damage. Excessive HOCl-production is implicated in the progression of many human diseases, including chronic inflammation, atherosclerosis and cancer and in bacterial interactions with the human immune system.

Public Health Relevance

The project proposed in this application will provide insights into how bacteria sense and respond to the oxidative stress effects of hypochlorous acid, the active antimicrobial component of bleach. This work is relevant to human health not only because bleach is a commonly used disinfectant, but also because hypochlorous acid is an important antimicrobial compound produced by the white blood cells of the immune system.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM096613-01A1
Application #
8202428
Study Section
Special Emphasis Panel (ZRG1-F13-C (20))
Program Officer
Bender, Michael T
Project Start
2011-09-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$48,398
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Gray, Michael J; Jakob, Ursula (2015) Oxidative stress protection by polyphosphate--new roles for an old player. Curr Opin Microbiol 24:1-6
Dahl, Jan-Ulrik; Gray, Michael J; Jakob, Ursula (2015) Protein quality control under oxidative stress conditions. J Mol Biol 427:1549-63
Gray, Michael J; Wholey, Wei-Yun; Wagner, Nico O et al. (2014) Polyphosphate is a primordial chaperone. Mol Cell 53:689-99
Knoefler, Daniela; Leichert, Lars I O; Thamsen, Maike et al. (2014) About the dangers, costs and benefits of living an aerobic lifestyle. Biochem Soc Trans 42:917-21
Gray, Michael J; Wholey, Wei-Yun; Jakob, Ursula (2013) Bacterial responses to reactive chlorine species. Annu Rev Microbiol 67:141-60