The mechanisms of 4-HNE mediated host-microbe interactionsdline

摘要 单核细胞增多性李斯特菌(Lm)是一种革兰氏阳性、机会性、胞内致病菌，可引起食物 天生的疾病。鉴于其良好的感染周期和遗传适应性，单核细胞增多性乳杆菌提供了 一个强大的工具，以询问宿主病原体相互作用的基本方面。我们实验室最近的工作 已经发现LM和其他病原体诱导产生有毒的醛4-羟基-2-壬烯醛 (4-HNE)。我们已经发现，在接触4-HNE后，LM诱导了一组特定的基因， 与这种有机体采用的特定解毒策略一致。在这里，我们建议审问 4-HNE生产在细菌生长限制中的作用及促进细菌生长的对策 感染。在目标I中，我们建议探索MARR转录因子在协调 对4-HNE暴露的转录反应。在目标2中，我们将询问4-HNE的分子机制。 用LM氧化还原酶解毒。在目标III中，我们将使用李斯特氏菌病的小鼠模型来表征 4-HNE对细菌感染结局的影响。这些研究将共同确定分子机制。 4-HNE的LM解毒作用，并确定其在感染期间对抗细菌的作用。

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.