The mechanisms of 4-HNE mediated host-microbe interactionsdline

4-HNE介导的宿主-微生物相互作用的机制

基本信息

批准号：
9221802
负责人：
Joshua Woodward
金额：
$ 18.44万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9221802
关键词：
4 hydroxynonenal Affect Aldehydes Alkylation Alzheimer&apos s Disease Amino Acids Antimicrobial Effect Atherosclerosis Bacteria Bacterial Infections Bacterial Model Biochemical Cells Chemicals Cysteine DNA Binding Disease Drug Metabolic Detoxication Exhibits Gene Expression Regulation Genes Genetic Genetic Transcription Genetic study Genomic Instability Glutathione Growth Health Histidine Human Immune response In Vitro Infection Infectious Agent Inflammation Ligands Lipids Listeria monocytogenes Listeriosis Lysine Malignant Neoplasms Measures Mediating Membrane Metabolism Microbe Modeling Modification Molecular N-terminal Nucleic Acids Nucleotides Organism Outcome Oxidation-Reduction Oxidoreductase Paper Pathogenicity Pathway interactions Physiological Polyunsaturated Fatty Acids Predisposition Production Proteins Reaction Reactive Oxygen Species Regulon Resistance Respiratory Burst Role Site Soil Sterility Testing Toxic effect Transcriptional Activation Virulence Work antimicrobial base biological adaptation to stress combat foodborne illness in vivo microbial microorganism mouse model oxidation pathogen protein function response sensor tissue culture tool transcription factor

项目摘要

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.

抽象的单核细胞增生李斯特菌 (Lm) 是一种革兰氏阳性、机会性、细胞内细菌病原体，可引起食物中毒传染疾病。鉴于其明确的感染周期和遗传适应性，单核细胞增生利斯特氏菌提供了询问宿主病原体相互作用的基本方面的强大工具。我们实验室最近的工作发现 Lm 以及其他病原体会诱导有毒醛 4-羟基-2-壬烯醛的产生 (4-HNE) 感染期间。我们发现 Lm 在暴露于 4-HNE 后会诱导一组特定的基因，与该生物体采用的特定解毒策略一致。在此我们建议询问 4-HNE产生对细菌生长限制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 II 中，我们将探究 4-HNE 的分子机制 Lm 氧化还原酶解毒。在目标 III 中，我们将使用李斯特菌病小鼠模型来表征 4-HNE 对细菌感染结果的影响。这些研究将共同确定分子机制 Lm 对 4-HNE 解毒的影响，并确定其在感染期间对抗细菌的作用。