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Listeria monocytogenes physiology and host pathogen interactions

单核细胞增生李斯特氏菌生理学和宿主病原体相互作用

基本信息

批准号：
10330555
负责人：
Joshua Woodward
金额：
$ 49.11万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10330555
关键词：
4 hydroxynonenal Actins Adenosine Monophosphate Affinity Aldehydes Antimicrobial Effect Antimicrobial Resistance Bacteria Bacterial Infections Binding Biochemical Biological Response Modifiers Bone Marrow Cells Cytosol Detection Disease Dissection Enzymes Eukaryotic Cell Exhibits Exposure to Funding Gallbladder Genes Genetic Genetic Transcription Genetic study Glean Grant Growth Health Host Defense Human Immune Immune response In Vitro Individual Infection Inflammation Inflammatory Response Innate Immune Response Innate Immune System Listeria monocytogenes Mediating Mediator of activation protein Membrane Transport Proteins Modeling Molecular Mus NF-kappa B NFKB Signaling Pathway Nitric Oxide Nitric Oxide Synthase Nucleotides Organism Pathogenesis Pattern recognition receptor Periodicity Physiology Predisposition Process Production Proteins Public Health Reactive Nitrogen Species Resistance Role Second Messenger Systems Signal Transduction Testing Toxic effect Virulence Whole Organism Analysis antimicrobial base cell motility fitness foodborne foodborne illness genome-wide human pathogen immune activation in vivo insight macrophage microbial mouse model novel pathogen pathogenic bacteria polymerization resistance factors resistance mechanism response tissue culture tool transmission process transposon sequencing

项目摘要

ABSTRACT Listeria monocytogenes 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 intracellular bacterial pathogenesis and the host immune response to invasion by intracellular pathogens. L. monocytogenes that enter into the host cell cytosol secrete the second messenger signaling nucleotide, c-di-AMP, resulting in innate immune activation by the host cell. We recently identified the host protein RECON as a key mediator of this response. RECON is an enzyme whose activity is inhibited by c-di-AMP. C-di-AMP inhibition of RECON results in the accumulation of the ROS byproduct 4-hydroxy-2-nonenal (4-HNE), which augments NF-kB activation, resulting in elevated nitric oxide synthase expression and NO production during infection. Intriguingly, we have revealed that NO produced by the host cell promotes L. monocytogenes intracellular motility, rather than restricting bacterial growth, and that L. monocytogenes exhibits extreme NO resistance. Additionally, preliminary studies have revealed that 4-HNE is ubiquitously induced by eukaryotic cells following exposure to bacteria and that this reactive aldehyde exhibits antimicrobial effects on bacteria analogous to NO. Furthermore, L. monocytogenes exhibits extreme resistance to the antimicrobial effects of 4-HNE and induces a specific transcriptional response to 4-HNE exposure, which we hypothesize promotes survival within the infected host. We have begun in vitro biochemical studies, in vivo forward genetic studies, and the murine models of infection to interrogate the mechanisms by which L. monocytogenes counteracts the antimicrobial effects of NO and 4-HNE and utilizes NO to promote virulence. In Aim I, we will interrogate the mechanisms used by L. monocytogenes to detoxify and counteract the antimicrobial effects of 4-HNE. In Aim II, we propose to detail the molecular mechanisms of NO resistance and the impacts on bacterial virulence. Finally, in Aim III we will detail the mechanism of NO induced L. monocytogenes actin- based motility and explore the in vivo impacts of this process on bacterial invasion and dissemination. Together these studies will define the molecular mechanisms of exquisite antimicrobial innate immune responses employed by L. monocytogenes to promote survival within the eukaryotic host. .

摘要