The mechanisms of 4-HNE mediated host-microbe interactionsdline

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ABSTRACT 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.