Understanding the immunometabolic response to Klebsiella pneumonia infection

了解肺炎克雷伯菌感染的免疫代谢反应

基本信息

批准号：
10448948
负责人：
Tania Wong Fok Lung
金额：
$ 12.22万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448948
关键词：
Acute Address Anti-Inflammatory Agents Antibiotic Resistance Antimicrobial Resistance Area Automobile Driving Bacteria Bacterial Genes Bacterial Infections COVID-19 pandemic Career Choice Cells Chemicals Chronic Clinical Development Effector Cell Failure Flow Cytometry Foundations Future Gene Expression Generations Genes Genetic Genetic Transcription Genomics Global Change Glucose Goals Homeostasis Hospitals Image Immune Immune response Immunosuppression In Vitro Indolent Infection Inflammatory Response Investigation Klebsiella Infections Klebsiella pneumoniae Knockout Mice Knowledge Light Lung Lung infections Medicine Metabolic Metabolic Activation Metabolic Pathway Metabolic stress Metabolism Molecular Morbidity - disease rate Multi-Drug Resistance Mus Myeloid-derived suppressor cells New York Nosocomial pneumonia Outcome Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathogenesis Pathway interactions Pattern Presbyterian Church Production Property Proteomics Public Health Quantitative Reverse Transcriptase PCR Reactive Oxygen Species Regulatory T-Lymphocyte Research SARS-CoV-2 infection Signal Transduction Structure of parenchyma of lung Surface System Techniques Testing Therapeutic Therapeutic Agents Time Tumor-infiltrating immune cells Universities Up-Regulation Vision Work biological adaptation to stress carbapenem resistance chronic infection cytokine fatty acid oxidation immune function inflammatory marker inhibitor macrophage metabolome metabolomics monocyte mortality mutant neoplastic cell novel strategies pathogen pediatric department premature prevent programs recruit research study resistant Klebsiella pneumoniae response single-cell RNA sequencing success therapeutically effective transcriptome sequencing transcriptomics tumor tumor growth tumor metabolism tumorigenesis ventilator-associated pneumonia

项目摘要

Project summary/abstract Carbapenem-resistant Klebsiella pneumoniae (Kp) strains belonging to sequence type (ST) 258 have spread globally in the past decades. Their association with often-fatal ventilator-associated pneumonia is of urgent public health concern especially in light of the current COVID-19 pandemic. While numerous studies have focused on investigating antimicrobial resistance strategies, there is still a lack of effective therapeutic agents, which urges the need to better understand other factors that are crucial for Kp ST258 persistence. Kp ST258 strains differ from hypervirulent strains that induce rapidly fatal infections by instead causing subacute chronic infections. Failure to clear Kp ST258 is associated with the recruitment of monocytes (myeloid-derived suppressor cells, MDSCs) with anti-inflammatory properties similar to those that promote the growth of tumor cells during oncogenesis. Given that metabolic activities govern the function of immune cells, we hypothesize that Kp ST258 metabolism in a manner similar to tumor metabolism generates host metabolic stress and a milieu conducive to the generation and expansion of immunosuppressive cells. We found that Kp ST258 stimulates a unique host metabolic response during pulmonary infection that is characterized by the rapid depletion of glucose, stimulation of glutaminolysis and fatty acid oxidation (FAO) pathways that fuel oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS) production, and the accumulation of the antioxidative metabolite itaconate. This project offers a novel approach to develop therapeutic strategies drawing upon the host metabolic response to Kp ST258 as the main factor promoting chronic pulmonary infection. Specifically, aim 1 explores the dynamics of the host immunometabolic response to Kp ST258. Aim 2 seeks to investigate how this response promotes immunosuppression while aim 3 focuses on its direct effect on bacterial adaptation to and survival in the airway by driving global changes in bacterial gene expression including the upregulation of the Type Six Secretion System (T6SS) to counteract oxidative stress.

项目摘要/摘要抗碳青霉苯甲肺炎肺炎（KP）菌株属于序列类型（ST）258 在过去的几十年中，全球。他们与经常致命呼吸机相关的肺炎的关联是紧急的公众尤其是鉴于当前的19日大流行，尤其是健康的关注。众多研究重点是研究抗菌抗性策略，仍然缺乏有效的治疗剂需要更好地理解对KP ST258持久性至关重要的其他因素的需求。 KP ST258菌株不同从高呼吸菌株中引起迅速致命感染的菌株，而不是引起亚急性慢性感染。无法清除KP ST258与单核细胞的募集有关（髓样衍生的抑制细胞， MDSC）具有抗炎特性，类似于促进肿瘤细胞在肿瘤发生。鉴于代谢活性控制了免疫细胞的功能，我们假设KP ST258 与肿瘤代谢相似的方式代谢产生了宿主的代谢应激和有利于的环境免疫抑制细胞的产生和扩展。我们发现KP ST258刺激了独特的主机肺部感染期间的代谢反应，其特征是葡萄糖快速耗竭，刺激谷氨酰胺分解和脂肪酸氧化（FAO）途径，燃料氧化磷酸化（Oxphos）和活性氧（ROS）的产生以及抗氧化代谢产物依环酸盐的积累。这项目提供了一种新的方法，可以根据宿主代谢反应来制定治疗策略 KP ST258是促进慢性肺部感染的主要因素。具体来说，AIM 1探索动态宿主对KP ST258的免疫代谢反应的。 AIM 2试图调查这种反应如何促进 AIM 3的免疫抑制专注于对细菌适应和生存的直接影响通过推动细菌基因表达的全球变化，包括六型分泌的上调系统（T6SS）以抵消氧化应激。