Innate immune-mediated control of pulmonary Legionella pneumophila infection

先天免疫介导控制肺部嗜肺军团菌感染

基本信息

批准号：
10675707
负责人：
Sunny Shin
金额：
$ 48.19万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2015-11-16 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675707
关键词：
Ablation Acetyl Coenzyme A Address Alveolar Macrophages Anti-Bacterial Agents Antibiotic Resistance Automobile Driving Bacterial Infections Bacterial Pneumonia Cell physiology Cells Collaborations Communities Cytokine Signaling Data Defense Mechanisms Development Enzymes Epigenetic Process Epithelial Cells Funding Future Generations Genetic Transcription Granulocyte-Macrophage Colony-Stimulating Factor Granulocyte-Macrophage Colony-Stimulating Factor Receptors Histone Acetylation Hospitals Host Defense Host Defense Mechanism Immune In Vitro Infection Infection Control Inflammatory Inflammatory Response Innate Immune System Interleukin-1 Interleukin-1 Receptors Interleukin-1 alpha Interleukin-1 beta Interleukin-12 Interleukin-6 JAK2 gene Knowledge Lactate Dehydrogenase Legionella Legionella pneumophila Legionnaires&apos Disease Licensing Lung Mediating Metabolic Morbidity - disease rate Myeloid Cells Nosocomial pneumonia Production Protein Biosynthesis Publishing Receptor Signaling Research Role Signal Transduction Source Stat5 protein TNF gene Testing Therapeutic Time Transcriptional Activation Translations Type IV Secretion System Pathway Vaccines Virulence Virulence Factors aerobic glycolysis alveolar epithelium antimicrobial cell type community acquired pneumonia cytokine defined contribution design epigenetic marker immune clearance improved in vivo innate immune mechanisms insight monocyte mortality mouse model novel pathogen pathogenic bacteria pathogenic microbe programs response therapeutically effective

项目摘要

Project Summary Intracellular bacterial pathogens such as Legionella pneumophila, an important cause of community- and hospital-acquired pneumonia, are responsible for significant morbidity and mortality worldwide. As the spread of broad-spectrum antibiotic resistance among bacterial pathogens is escalating, discovery of novel innate immune defense mechanisms may hold the key for future therapeutic approaches to deal with this increasing threat. Intracellular pathogens deploy virulence factors to disable many immune cell functions. To win this battle, the host must overcome this subversion, through as yet poorly defined mechanisms. To address this critical gap in knowledge, we seek to define the parameters of successful innate immune clearance of Legionella. Legionella replicates within alveolar macrophages by using its type IV secretion system to deliver bacterial effectors, several of which inhibit host protein synthesis. Several effectors inhibit host protein synthesis. Despite this block in host translation, Legionella infection paradoxically enhances production of inflammatory cytokines. In the previous funding period, we demonstrated that Legionella-infected alveolar macrophages are able to synthesize and release IL-1; moreover, IL-1 receptor (IL-1R) signaling was required for robust production of TNF and IL-12 by bystander myeloid cells. Intriguingly, our newly published study show for the first time that IL-1R signaling in alveolar epithelial cells induces production of granulocyte-macrophage colony-stimulating factor (GM-CSF), which was required for bystander cytokine production and bacterial clearance. Intriguingly, while GM-CSF acts as a potent inflammatory cytokine in host defense against a broad spectrum of pathogens, our findings show for the first time that GM-CSF metabolically reprograms monocytes to undergo aerobic glycolysis, thereby promoting cytokine production. We will test the hypothesis that alveolar epithelium-derived GM-CSF metabolically reprograms monocytes to amplify epigenetic changes that enhance TLR-driven cytokine production and control of infection. In this renewal, we propose three Aims to first: define which cell types produce and respond to GM-CSF, second: understand the role of GM-CSF-mediated metabolic reprogramming in host defense, and third: define how GM-CSF and TLR signaling collaborate to promote cytokine production. Together, these studies will define novel innate immune mechanisms employed by the host to surmount pathogen-encoded virulence activities. The proposed research will therefore provide vital insight into mechanisms of host defense that are utilized against broad classes of microbial pathogens and aid development of improved anti-microbial therapeutics and vaccines.

项目概要细胞内细菌病原体，例如嗜肺军团菌，是社区和社区感染的重要原因医院获得性肺炎是造成全世界显着发病率和死亡率的原因。随着传播细菌病原体的广谱抗生素耐药性正在升级，新的先天性抗生素的发现免疫防御机制可能是未来治疗方法的关键，以应对这种日益增加的疾病威胁。细胞内病原体利用毒力因子来禁用许多免疫细胞功能。为了赢得这场在战斗中，宿主必须通过尚未明确的机制克服这种颠覆。为了解决这个问题知识的关键差距，我们试图定义成功的先天免疫清除的参数军团菌。军团菌通过使用其 IV 型分泌系统在肺泡巨噬细胞内复制以传递细菌效应器，其中一些抑制宿主蛋白质合成。几种效应子抑制宿主蛋白合成。尽管宿主翻译受到阻碍，军团菌感染反而增强了炎症细胞因子。在之前的资助期间，我们证明了军团菌感染的肺泡巨噬细胞能够合成并释放IL-1；此外，还需要 IL-1 受体 (IL-1R) 信号传导用于旁观者骨髓细胞大量产生 TNF 和 IL-12。有趣的是，我们新发表的研究表明首次发现肺泡上皮细胞中的 IL-1R 信号传导诱导粒细胞-巨噬细胞的产生集落刺激因子 (GM-CSF)，这是旁观者细胞因子产生和细菌产生所必需的清除。有趣的是，虽然 GM-CSF 在宿主防御广泛的炎症反应中充当有效的炎症细胞因子，病原体谱，我们的研究结果首次表明 GM-CSF 通过代谢重新编程单核细胞进行有氧糖酵解，从而促进细胞因子的产生。我们将检验以下假设：肺泡上皮来源的 GM-CSF 通过代谢重新编程单核细胞，放大表观遗传变化，从而增强 TLR 驱动的细胞因子产生和感染控制。在这次更新中，我们首先提出三个目标：定义哪些细胞类型产生 GM-CSF 并对其作出反应，第二：了解 GM-CSF 介导的作用宿主防御中的代谢重编程，第三：定义 GM-CSF 和 TLR 信号如何协作促进细胞因子的产生。这些研究将共同定义所采用的新型先天免疫机制由宿主克服病原体编码的毒力活动。因此，拟议的研究将提供对用于对抗广泛的微生物病原体的宿主防御机制的重要见解并帮助开发改进的抗微生物疗法和疫苗。