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Molecular and Metabolic inter-kingdom actions of a bacterial quorum sensing signal in promotion of host tolerance/resilience.

细菌群体感应信号在促进宿主耐受性/弹性方面的分子和代谢界间作用。

基本信息

批准号：
10326383
负责人：
LAURENCE G RAHME
金额：
$ 67.1万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326383
关键词：
3-Dimensional ATP Synthesis Pathway Acetyl Coenzyme A Acetylation Adoptive Transfer Anabolism Animal Model Antibiotics Autophagocytosis Bacteria Bacterial Infections Bacterial Model Behavior Biological Bone Marrow Cells Cells ChIP-seq Characteristics Chemistry Chromatin Chronic Citric Acid Cycle Clinical Communication ESKAPE pathogens Energy Metabolism Epigenetic Process Genome Goals HDAC1 gene Health Histone Acetylation Histone Deacetylase Histone H3 Human Immune Immune response Immune system Immunologic Memory In Vitro In Vivo NMR Spectroscopy Infection Inflammation Inflammatory Inflammatory Response Knowledge Ligase Lysine Maintenance Mediating Mediator of activation protein Memory Metabolic Metabolism Microbe Microbial Biofilms Modeling Molecular Mus Oligonucleotides Pathogenicity Patients Pharmaceutical Preparations Pharmacology Prokaryotic Cells Promoter Regions Pseudomonas aeruginosa Publications Regulation Relapse Resistance Role Series Signal Transduction Signaling Molecule System TNF gene Testing Time Tissues Training Variant Visualization Work antibiotic tolerance chronic infection clinically relevant cytokine effective therapy epigenetic memory epigenetic regulation epigenome experimental study fatty acid biosynthesis fitness histone acetyltransferase immunopathology immunoregulation improved in vivo inhibitor insight knock-down macrophage metabolome novel pathogen pathogenic bacteria persistent bacterial infection promoter quorum sensing reconstitution resilience small molecule therapeutic development therapy development

项目摘要

Our long-term goal is to develop treatments that may improve resilience to pathogen damage in patients with serious infections, including chronic and relapsing bacterial infections, for which effective treatments are lacking. Bacterial quorum sensing (QS) signals are important mediators of immunomodulation. However, it remains unclear how microbes utilize immunomodulatory signals to maintain a long-term presence and thwart clearance and how hosts avoid harmful inflammatory response to a pathogen’s presence. In our previous work, we identified a small volatile QS molecule excreted by Pseudomonas aeruginosa (PA), 2-aminoacetophenone (2-AA), that acts as an inter-kingdom “infochemical” to alter immune responses and metabolism in a manner that trains the host to increase host tolerance/resilience (HT/R), which is defined as the host's ability to cope with bacterial encounter without a consequent reduction in fitness; these alterations allow the pathogen to avoid elimination and persist in mammalian tissues. The specific goal of this application is to decipher paradigmatically the mode of action of a bacterial product on host metabolome and epigenome in order to gain insights into the first mechanistic example of a QS molecule that reprograms the host metabolome and epigenome to promote HT/R. Our hypothesis is that the long-lasting immunomodulatory changes exerted by 2-AA through the sustained activity of histone deacetylase 1 (HDAC1) derive from 2-AA–promoted metabolic alterations; and that the interplay between host metabolome and epigenome contribute to the mutual bacterial-host fitness that defines HT/R. We propose to achieve our goal through experiments employing PA, a recalcitrant Gram-negative ESKAPE bacterium that defies eradication by antibiotics, forms biofilms, and exemplifies current clinically problematic pathogens. In Aim 1, we will examine how 2-AA maintains epigenetic reprogramming by assessing the molecular mechanisms of long-term immunomodulation in immune memory in vivo promoted by 2-AA tolerization, and determine the occurring metabolic changes by performing functional studies. In Aim 2, we will interogate the capacity of 2-AA to regulate macrophage autophagy in tissues and conduct a meticulous analysis of the key host players and cellular mechanisms that permit bacterial persistence. In Aim 3, using murine in vitro and in vivo systems in addition to human primary macrophages, we will evaluate the interplay between 2-AA promoted epigenetic control and metabolic alterations by undertaking molecular and functional approaches. The impact of these alterations in bacterial persitence, histone acetylation, energy metabolism and the efficacy of our novel anti-2AA compound will be asssessed using clinically relevant animal models of infection. In Aim 4, we will seek to identify 2-AA’s direct target using click chemistry. The proposed elucidation of “host tolerance training” mechanisms is intended to improve our understanding of HT/R that remains extremely limited. In this context, the findings may offer opportunities for being applied to the development of therapeutic treatments that can train the host to augment resilience to infection. In principle, the knowledge to be obtained could be applicable to persistent infections triggered also by other bacteria because QS is broadly conserved among Gram-negative and Gram-positive human bacterial pathogens and, as such, 2-AA-like molecules are likely to exist in other bacteria.

我们的长期目标是开发治疗方法，提高严重感染患者对病原体损伤的抵抗力，包括缺乏有效治疗的慢性和复发性细菌感染。细菌群体感应（QS）信号是重要的免疫调节介质。然而，目前尚不清楚微生物如何利用免疫调节信号来维持长期存在并阻碍清除，以及宿主如何避免对病原体存在的有害炎症反应。在我们之前的工作中，我们鉴定了由铜绿假单胞菌（PA）分泌的小的挥发性QS分子，2-氨基苯乙酮（2-AA），其作为界间“信息化学品”以训练宿主增加宿主耐受性/恢复力（HT/R）的方式改变免疫应答和代谢，HT/R被定义为宿主科普细菌遭遇而不随之降低适应性的能力;这些改变使得病原体能够避免消除并在哺乳动物组织中持续存在。本申请的具体目标是以范例方式解读细菌产物对宿主代谢组和表观基因组的作用模式，以便深入了解QS分子的第一个机制实例，该QS分子重编程宿主代谢组和表观基因组以促进HT/R。我们的假设是，2-AA通过组蛋白去乙酰化酶1（HDAC 1）的持续活性产生的持久的免疫调节变化来自2-AA促进的代谢改变;宿主代谢组和表观基因组之间的相互作用有助于定义HT/R的相互细菌-宿主适应性。我们建议通过采用PA的实验来实现我们的目标，PA是一种革兰氏阴性ESKAPE细菌，它无法通过抗生素根除，形成生物膜，并消除当前临床上有问题的病原体。在目标1中，我们将通过评估2-AA耐受化促进的体内免疫记忆中的长期免疫调节的分子机制来研究2-AA如何维持表观遗传重编程，并通过进行功能研究来确定发生的代谢变化。在目标2中，我们将研究2-AA调节组织中巨噬细胞自噬的能力，并对允许细菌持久存在的关键宿主参与者和细胞机制进行细致的分析。在目标3中，除了人原代巨噬细胞外，还使用小鼠体外和体内系统，我们将通过进行分子和功能方法来评估2-AA促进的表观遗传控制和代谢改变之间的相互作用。这些改变对细菌持久性、组蛋白乙酰化、能量代谢的影响以及我们的新型抗2AA化合物的功效将使用临床相关的感染动物模型进行评估。在目标4中，我们将寻求使用点击化学来识别2-AA的直接靶标。提出的“宿主耐受性训练”机制的阐明旨在提高我们对HT/R的理解，这仍然是非常有限的。在这种情况下，这些发现可能提供了应用于开发治疗性治疗的机会，这些治疗性治疗可以训练宿主增强对感染的抵抗力。原则上，所获得的知识可适用于也由其他细菌触发的持续性感染，因为QS在革兰氏阴性和革兰氏阳性人类细菌病原体中广泛保守，因此，2-AA样分子可能存在于其他细菌中。