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：
9397512
负责人：
Joshua Woodward
金额：
$ 18.39万
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 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9397512
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，会引起食物生病。鉴于其特征良好的感染周期和遗传性不适，单核细胞增生李斯特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。我们实验室的最新工作发现LM以及其他病原体诱导有毒醛4-羟基-2-非烯烷的产生（4-HNE）感染。我们发现，LM在4-HNE暴露后诱导一组特定的基因，与该生物采用的特定排毒策略一致。在这里我们建议讯问 4-HNE产生在细菌生长限制和细菌对策中的作用以促进感染。在目标I中，我们建议探索MARR转录因子在策划的作用对4-HNE暴露的转录反应。在AIM II中，我们将询问4-HNE的分子机制 LM氧化还原酶解毒。在AIM III中，我们将使用李斯特氏菌病的鼠模型来表征 4-HNE对细菌感染结果的影响。这些研究将共同定义分子机制通过LM排毒的4-HNE排毒，并确定其在感染过程中打击细菌中的作用。