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

• 批准号: 10437007
• 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
• 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/10437007
• 关键词: Acetyl Coenzyme A; Address; Alveolar Macrophages; Anti-Bacterial Agents; Antibiotic Resistance; Automobile Driving; Bacterial Infections; Cell physiology; Cells; Community Hospitals; 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; IL1R1 gene; 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' Disease; Licensing; Lung; Mediating; Metabolic; Morbidity - disease rate; Myelogenous; Myeloid Cells; Nosocomial pneumonia; Production; Protein Biosynthesis; Proteins; 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; response; therapeutically effective

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.

项目摘要 细胞内细菌病原体，如嗜肺军团菌，社区的重要原因-以及 医院获得性肺炎是全世界发病率和死亡率的主要原因。随着疫情的蔓延 细菌病原体广谱抗生素耐药性升级，发现新的先天 免疫防御机制可能是未来处理这种增加的治疗方法的关键 威胁。细胞内的病原体部署毒力因子来使许多免疫细胞功能失效。为了赢得这场胜利 战斗中，东道主必须通过尚未定义的机制来克服这种颠覆。要解决这个问题 关键的知识差距，我们寻求定义成功清除先天免疫的参数 军团菌。军团菌利用其IV型分泌系统在肺泡巨噬细胞内复制 细菌效应物，其中几个抑制宿主蛋白质的合成。几种效应器抑制宿主蛋白 综合。尽管宿主翻译受到这种阻碍，军团菌感染却矛盾地增强了 炎性细胞因子。在之前的资助期间，我们证明了感染军团菌的肺泡 巨噬细胞能够合成和释放IL-1；此外，IL-1受体(IL-1R)信号也是必需的 以增强旁观者骨髓细胞产生肿瘤坏死因子和白介素12的能力。耐人寻味的是，我们新发表的研究表明 肺泡上皮细胞中IL-1R信号首次诱导粒细胞-巨噬细胞产生 集落刺激因子(GM-CSF)，旁观者产生细胞因子和细菌所需的 通行证。耐人寻味的是，当GM-CSF作为一种有效的炎症细胞因子在宿主防御广泛的 病原体谱，我们的发现首次表明GM-CSF对单核细胞进行代谢重新编程 有氧糖酵解，从而促进细胞因子的产生。我们将检验这样的假设：肺泡 上皮源性GM-CSF代谢性地重新编程单核细胞以放大表观遗传变化 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 哪些细胞类型产生和应答GM-CSF，第二：了解GM-CSF介导的作用 宿主防御中的代谢重新编程，第三：定义GM-CSF和TLR信号如何合作 促进细胞因子的产生。总之，这些研究将确定采用的新的先天免疫机制。 由寄主克服病原体编码的毒力活动。因此，拟议的研究将提供 对寄主防御机制的重要洞察，这些机制可用于抵御广泛类别的微生物病原体 并帮助开发改进的抗微生物疗法和疫苗。