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: 10206605
• 负责人: Julia K. Bohannon
• 金额: $ 17.3万
• 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/10206605
• 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; Infection; Infection prevention; Knowledge; Leukocytes; Life; Mediating; Metabolic; Mitochondria; Modification; Molecular; Mus; Myeloid Cells; Nosocomial Infections; Oxidative Stress; Patients; 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; clinical efficacy; clinically relevant; drug resistant pathogen; immunomodulatory therapies; immunoregulation; improved; macrophage; 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.

项目摘要 由于屏障丧失，院内感染仍然是严重烧伤患者死亡的主要原因， 配对免疫和抗生素耐药病原体的高流行率。免疫调节策略旨在 非常需要增强宿主的反应。有证据表明，Toll样受体（TLR）激动剂 作为免疫剂有很大希望实现这一目标。用TLR 4激动剂引发增强 通过诱导， “训练免疫”的概念，先天免疫细胞对随后的感染性疾病变得更加敏感。 刺激。TLR 4介导的训练免疫的特征是代谢重编程和线粒体前体细胞凋亡。 在巨噬细胞中的扩张，增强抗菌反应。细胞信号传导机制负责 TLR介导的训练性免疫及烧伤对先天性巨噬细胞代谢和线粒体功能的影响 白细胞仍有待阐明。我们的研究项目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感染， 烧伤后触发训练免疫保护的可能性。为了实现这些目标，我们将 三个综合项目：项目1将调查严重烧伤和烧伤后感染对 骨髓细胞免疫代谢和线粒体功能。我们将评估代谢，线粒体， 抗微生物功能，包括糖酵解和氧化应激能力，线粒体， DRIAL内容和功能分析，以及小鼠和人白细胞中的差异基因表达， 节省大量每天往返于这个项目将扩大我们对烧伤诱导的白细胞失调的分子机制的理解， 功能项目2将评估TLR激动剂诱导白细胞免疫训练的机制。 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， 通路阻断，以研究TLR介导的诱导训练性肌萎缩的分子机制。 烧伤后社区我们将检查TLR激动剂诱导白细胞训练免疫的能力， 烧伤病人该项目将填补我们对机制的理解方面的关键空白， 对烧伤病人感染的抵抗力。项目3将阐明靶向TLR信号传导的潜力 烧伤相关感染的临床相关模型中的治疗获益途径。我们会- 确定临床上可应用的TLR激动剂在赋予针对多种病原体的保护方面的功效 在烧伤患者中普遍存在。我们将评估保护持续时间，重复治疗后保护的延长， 以及TLR激动剂是否可以促进感染发作后的感染清除。该项目将揭示潜力- 临床开发中应考虑的介导预防医院感染的药物靶点 烧伤患者的感染。这些项目将提高我们对烧伤引起的先天性免疫缺陷的理解， 功能和识别治疗靶点，以提高免疫力和防止烧伤相关感染。