Listeria monocytogenes (Lm) is a gram-positive, opportunistic, intracellular bacterial pathogen that causes food borne illness. Given its well-characterized infection cycle and genetic amenability, L. monocytogenes provides a powerful tool to interrogate the fundamental aspects of host pathogen interactions. Recent work in our lab has found that Lm as well as other pathogens induce the production of the toxic aldehyde 4-hydroxy-2-nonenal (4-HNE) during infection. We have found that Lm induces a specific set of genes following 4-HNE exposure, consistent with a specific detoxification strategy employed by this organism. Here we propose to interrogate the role of 4-HNE production on bacteria growth restriction and the bacterial countermeasures to promote infection.
In Aim I, we propose to explore the role of a MarR transcription factor in orchestrating the transcriptional response to 4-HNE exposure.
In Aim II, we will interrogate the molecular mechanisms of 4-HNE detoxification by Lm oxidoreductases.
In Aim III, we will use a murine model of Listeriosis to characterize the effects of 4-HNE on bacterial infection outcome. Together these studies will define the molecular mechanisms of 4-HNE detoxification by Lm and determine its role in combating bacteria during infection.

Public Health Relevance

Bacterial pathogens remain on of the largest human health burdens in the 21st century. By characterizing the mechanism of host-pathogen interactions using the model intracellular bacterium L. monocytogenes we will define the fundamental mechanisms employed by intracellular pathogens to promote disease and the host response to these infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI127833-02
Application #
9397512
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mills, Melody
Project Start
2016-12-15
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195