Enhancing Resistance to Infection after Burn Injury with TLR Agonists

使用 TLR 激动剂增强烧伤后的感染抵抗力

• 批准号: 9417030
• 负责人: Julia K. Bohannon
• 金额: $ 31.6万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9417030
• 关键词: Acute; Affect; Agonist; Antibiotic-resistant organism; Antimicrobial Effect; Apoptosis; Bacterial Antibiotic Resistance; Bacterial Infections; Blood; Bone Marrow; Burn injury; Candida albicans; Cause of Death; Cell Adhesion Molecules; Cessation of life; Data; Exposure to; FRAP1 gene; Goals; Hospitalization; Hospitals; Host Defense Mechanism; Host resistance; Immune response; Immunity; Immunomodulators; Impairment; Incidence; Infection; Infection prevention; Injury; Innate Immune Response; Knockout Mice; Knowledge; Leukocytes; Life; Ligands; Lipid A; Mediating; Metabolism; Microbe; Modeling; Molecular; Mus; Natural Immunity; Neutrophil Infiltration; Outcome; Pathway interactions; Patients; Phagocytosis; Phase; Physiological; Play; Poly I-C; Predisposition; Prevalence; Prevention approach; Production; Pseudomonas aeruginosa; Resistance; Resistance to infection; Role; Sepsis; Severities; Signal Pathway; Signal Transduction; Site; Staphylococcus aureus; Systemic infection; TLR3 gene; TLR4 gene; Testing; Therapeutic; Topical Antibiotic; Vulnerable Populations; Wound Infection; antimicrobial; arm; base; clinically relevant; cytokine; immunoregulation; improved; injured; innovation; insight; neutrophil; novel strategies; pathogen; recruit; response; skin barrier; trafficking

ABSTRACT Infection is the leading cause of death and prolonged hospitalization in severely burned patients that survive the acute phase of injury. Loss of the skin barrier, impaired innate immunity and the prevalence of antibiotic resistant bacteria increase the susceptibility of burn patients to serious infection, leading to a great need for immunomodulation strategies aimed at priming the host response in these patients. Priming with TLR4 ago- nists have been shown to augment neutrophil antimicrobial responses and enhance resistance against infec- tion after severe burn injury in mice. However, the role of the classical MyD88- and TRIF-dependent TLR sig- naling cascades in mediating this protection, are not fully understood. Preliminary studies support a primary role for MyD88-signaling in mediating antimicrobial responses, potentially through augmentation of leukocyte metabolism via induction of the PI3K signaling pathway, but the cellular and molecular mechanisms involved are unclear. The long-term goal of this project is to better understand the distinct roles of MyD88- and TRIF- dependent signaling during immunomodulation with TLR ligands. The overall objective is to identify potential immunomodulatory strategies as a means of offering protection against infection in burn patients. The central hypothesis is that Myd88-dependent signaling is crucial in facilitating TLR agonist-induced augmenta- tion of antimicrobial responses, and that MyD88-specific TLR agonists will be highly effective in im- proving neutrophil-mediated resistance to infection after burn injury. This hypothesis will be tested by three specific aims: Aim 1: To determine whether treatment with TLR agonists that selectively activate the MyD88- and TRIF-signaling pathways can improve the host response to diverse pathogens in burned mice. This aim will be achieved by priming burned mice with MyD88-specific (CpG) or Trif-specific (PolyI:C) agonists and evaluating outcome and clearance of infection after challenge with S. aureus, C. albicans and P. aerugino- sa. Aim 2: To define the cellular mechanisms by which treatment with MyD88- and TRIF-specific agonists af- fect innate immune responses to infection after burn. Burned mice will be primed with pathway specific ago- nists as in Aim 1, and neutrophil expansion, trafficking, activation, and antimicrobial functions will be analyzed. Aim 3: To define the molecular mechanisms by which TLR agonists augment antimicrobial immunity after burn injury. In this aim, activation of the PI3K/Akt/mTOR/Hif-1α signaling pathway by TLR agonists and the role of this signaling pathway in mediating antimicrobial responses via augmentation of leukocyte metabolism will be examined. The studies proposed in this project represent an entirely novel approach to the prevention of infec- tion and sepsis which is translational and highly innovative. These studies are significant in that they will also fill important gaps in knowledge by advancing our understanding of the cellular and molecular mechanisms by which TLR-based immunomodulators improve host resistance to acute life-threatening infections.

摘要 感染是导致严重烧伤患者死亡和延长住院时间的主要原因， 受伤的急性期。皮肤屏障丧失，先天免疫力受损，抗生素普遍使用 耐药细菌增加了烧伤患者对严重感染的易感性，导致对 免疫调节策略旨在引发这些患者的宿主反应。TLR 4前预充- nists已被证明能增强中性粒细胞的抗微生物反应，并增强对感染的抵抗力， 小鼠严重烧伤后的恢复情况。然而，经典的MyD 88和TRIF依赖性TLR sig的作用， 纳灵瀑布在调解这种保护，没有完全理解。初步研究表明， MyD 88信号在介导抗菌反应中的作用，可能通过增加白细胞 通过诱导PI 3 K信号通路来代谢，但涉及的细胞和分子机制 不清楚。该项目的长期目标是更好地了解MyD 88和TRIF的不同作用， 在用TLR配体进行免疫调节期间依赖信号传导。总体目标是确定潜在的 免疫调节策略作为一种保护烧伤患者免受感染的手段。中央 假设Myd 88依赖性信号传导在促进TLR激动剂诱导的扩增中是至关重要的， MyD 88特异性TLR激动剂将在免疫应答中非常有效。 证明了嗜中性粒细胞介导的对烧伤后感染的抗性。这一假设将由以下人员进行检验： 三个具体目的：目的1：确定用选择性激活TLR受体激动剂治疗是否能促进肿瘤细胞增殖。 MyD 88和TRIF信号通路可以改善烧伤小鼠对不同病原体的宿主反应。 该目的将通过用MyD 88特异性（CpG）或Trif特异性（PolyI：C）激动剂引发烧伤小鼠来实现 并评价用S.金黄色葡萄球菌C.白色念珠菌和铜绿假单胞菌- sa.目的2：确定MyD 88和TRIF特异性激动剂治疗AF的细胞机制。 影响烧伤后对感染的天然免疫反应。烧伤的小鼠将被注射特定途径的前- 如目的1所述，分析中性粒细胞扩增、运输、活化和抗微生物功能。 目的3：明确TLR激动剂增强烧伤后抗微生物免疫的分子机制 损伤在这个目标中，TLR激动剂对PI 3 K/Akt/mTOR/HIF-1α信号通路的激活以及TLR激动剂在PI 3 K/Akt/mTOR/HIF-1α信号通路中的作用， 这种通过增加白细胞代谢介导抗微生物应答的信号传导途径， 考察该项目中提出的研究代表了一种全新的预防感染的方法， 感染和败血症，这是翻译和高度创新。这些研究意义重大，因为它们也将 通过推进我们对细胞和分子机制的理解来填补知识的重要空白， 所述基于TLR的免疫调节剂改善宿主对急性危及生命的感染的抗性。