Protection Against Nosocomial Infections After Severe Burn Injury Through Trained Immunity

通过训练有素的免疫力预防严重烧伤后的医院感染

• 批准号: 10605193
• 负责人: Julia K. Bohannon
• 金额: $ 43.25万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605193
• 关键词: Agonist; Burn injury; Cause of Death; Cells; Drug Targeting; Exposure to; Functional disorder; Genetic; Goals; High Prevalence; Hospitalization; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunologic Memory; Immunotherapeutic agent; Immunotherapy; Impairment; Infection; Infection prevention; Knowledge; Leukocytes; Life; Macrophage; Mediating; Metabolic; Mitochondria; Modification; Molecular; Mus; Myeloid Cells; Nosocomial Infections; Oxidative Stress; Patients; Predisposition; Research; Resistance; Resistance to infection; Signal Pathway; Signal Transduction; Stimulus; TLR4 gene; Techniques; Therapeutic; Tissue-Specific Gene Expression; Toll-like receptors; Training; antimicrobial; burn model; clinical application; clinical development; clinically relevant; drug resistant pathogen; efficacy evaluation; immunomodulatory therapies; immunoregulation; improved; pathogen; programs; response; severe burns; therapeutic target

PROJECT SUMMARY Nosocomial infections remain the leading cause of death in severely burned patients due to barrier loss, im- paired immunity, and high prevalence of antibiotic resistant pathogens. Immunomodulatory strategies aimed at augmenting the host response are greatly needed. Evidence suggests that Toll-like receptor (TLR) agonists hold strong promise as immunotherapeutic agents to achieve that goal. Priming with TLR4 agonists enhances resistance against a variety of clinically relevant infections associated with severe burn injury in mice via induc- tion of “trained immunity” whereby innate immune cells become more responsive to subsequent infectious stimuli. TLR4-mediated trained immunity is characterized by metabolic reprogramming and mitochondrial ex- pansion in macrophages which boost antimicrobial responses. Cellular signaling mechanisms responsible for TLR-mediated trained immunity and the effect of burn injury on metabolic and mitochondrial function in innate leukocytes remains to be elucidated. Our research program aims to investigate immunomodulatory therapies for prevention of infection following severe burn by elucidating burn-induced immunometabolic dysfunction and the potential for triggering trained immunity for protection after burn. To achieve these goals, we will pursue three integrated projects: Project 1 will investigate the impact of severe burn and post-burn infection on myeloid cell immunometabolism and mitochondrial function. We will assess metabolic, mitochondrial, and antimicrobial function using a variety of techniques including glycolytic and oxidative stress capacity, mitochon- drial content and function analyses, and differential gene expression in mouse and human leukocytes after burn. This project will expand our understanding of molecular mechanisms behind burn-induced leukocyte dys- function. Project 2 will evaluate mechanisms by which TLR agonists induce trained immunity in leuko- cytes after burn. We will use genetic modification, TLR signaling pathway-selective agonism, and signaling pathway blockade to investigate the molecular mechanisms involved in TLR-mediated induction of trained im- munity after burn. We will examine the ability of TLR agonists to induce trained immunity in leukocytes from burn patients. This project will fill critical gaps in our understanding of mechanisms by which we can improve resistance to infections in burn patients. Project 3 will elucidate the potential of targeting TLR-signaling pathways for therapeutic benefit in clinically relevant models of burn-associated infection. We will de- termine the efficacy of clinically applicable TLR agonists in conferring protection against a variety of pathogens prevalent in burn patients. We will evaluate protection duration, extension of protection upon repeated therapy, and whether TLR agonists can promote infection clearance after infection onset. This project will reveal poten- tial drug targets that should be considered for clinical development for mediating protection against nosocomial infections in burn patients. These projects will enhance our understanding of burn-induced innate immune dys- function and identify therapeutic targets to improve immunity and protect against burn-related infections.

项目总结 医院感染仍然是严重烧伤患者死亡的主要原因，原因是屏障丧失。 配对免疫，以及抗药性病原体的高流行率。针对以下目标的免疫调节策略 增强宿主的反应是非常必要的。有证据表明，Toll样受体(TLR)激动剂 作为免疫治疗剂，人们对实现这一目标抱有很大希望。用TLR4激动剂预充可增强 诱导小鼠对与严重烧伤相关的各种临床相关感染的抵抗力 增强“训练有素的免疫力”，使先天免疫细胞对随后的感染反应更强。 刺激物。TLR4介导的训练性免疫以代谢重编程和线粒体活化为特征。 巨噬细胞中增强抗菌反应的泛素。细胞信号机制负责 TLR介导的训练性免疫及烧伤对天然代谢和线粒体功能的影响 白细胞仍有待阐明。我们的研究计划旨在研究免疫调节疗法 通过阐明烧伤诱导的免疫代谢功能障碍预防严重烧伤后的感染 烧伤后触发训练有素的免疫力进行保护的可能性。为了实现这些目标，我们将致力于 三个综合项目：项目1将调查严重烧伤和烧伤后感染对 髓系细胞免疫代谢与线粒体功能。我们将评估新陈代谢、线粒体和 使用各种技术的抗菌功能，包括糖酵解和氧化应激能力，有丝分裂素- 小鼠和人白细胞的含量和功能分析以及差异基因表达 烧了吧。这个项目将扩大我们对烧伤引起的白细胞异常的分子机制的理解。 功能。项目2将评估TLR激动剂诱导白血病患者训练性免疫的机制。 烧伤后的细胞。我们将使用基因修饰、TLR信号通路选择性激动剂和信号转导 阻断通路以研究TLR介导的训练性免疫诱导的分子机制。 燃烧后的社区生活。我们将检测TLR激动剂在白细胞中诱导训练性免疫的能力 烧伤病人。这个项目将填补我们对机制的理解上的重大空白，通过这些机制，我们可以改进 烧伤患者对感染的抵抗力。项目3将阐明以TLR信号为靶点的可能性 烧伤相关感染的临床相关模型的治疗效益途径。我们会去- 终止临床应用的TLR激动剂对多种病原体的保护作用 在烧伤患者中很常见。我们将评估保护期，重复治疗后保护的延长， 以及TLR激动剂是否能促进感染发生后的感染清除。这个项目将揭示潜力- 临床开发中应考虑的抗医院感染药物靶点 烧伤患者的感染。这些项目将增强我们对烧伤诱导的先天性免疫机能障碍的理解- 发挥作用并确定治疗目标，以提高免疫力和预防烧伤相关感染。