Augmentation of Innate Anti-Microbial Immunity by TLR4 Agonists

TLR4 激动剂增强先天抗微生物免疫力

• 批准号: 8423657
• 负责人: Perenlei Enkhbaatar
• 金额: $ 30.82万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-02 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423657
• 关键词: Acute; Agonist; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Area; Bacteria; Bacterial Infections; Blood; Bone Marrow; Burn injury; CSF3 gene; Catheters; Cause of Death; Cell Adhesion Molecules; Cessation of life; Chemotactic Factors; Chemotaxis; Clinical; Critical Illness; Defense Mechanisms; Dose; Frequencies; Goals; Hospitalization; Host resistance; Human; Immune response; Immunity; Immunomodulators; Individual; Infection; Infection prevention; Interferons; Intubation; Knowledge; Life; Lung; Mediating; Modeling; Molecular; Monitor; Mus; Neutrophil Infiltration; Pathway interactions; Patients; Phosphatidylinositols; Phosphotransferases; Pneumonia; Prevalence; Production; Pseudomonas aeruginosa; Receptor Signaling; Resistance to infection; Safety; Sepsis; Severities; Sheep; Signal Transduction; Site; Skin; Surface; Testing; Tissues; Toll-like receptors; Toxic effect; Translating; Translations; Vaccine Adjuvant; Venous; Work; Wound Infection; antimicrobial; bacterial resistance; base; clinical practice; clinically relevant; high risk; immune function; improved; monophosphoryl lipid A; neutrophil; preclinical study; public health relevance; research study; response; toll-like receptor 4; trafficking; treatment strategy; wound

DESCRIPTION (provided by applicant): Large surface area burns cause loss of the protective skin barrier and dysregulation of antimicrobial defense mechanisms resulting in ideal conditions for colonization of burn wounds and dissemination of bacteria into blood, lung and other tissues. Although topical and systemic antibiotics are routinely used, sepsis is the most common cause of prolonged hospitalization and death in burn patients that survive the initial insult. The frequency and severity of sepsis is exacerbated by the increasing prevalence of antibiotic resistant bacteria. Therefore, there is a need for new treatments to improve resistance to infection in severely burned patients. Our studies show that treatment with the toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) is effective in improving innate host resistance to Pseudomonas aeruginosa burn wound sepsis in mice. MPLA has low toxicity and is currently used widely as a vaccine adjuvant in the clinical setting. However, the mechanisms by which MPLA augments the host response to systemic bacterial infections are not well understood and further work is needed to translate the use of MPLA in high risk patients to the clinical setting. The goal of this project is to identify the cellular and molecular mechanisms by which TLR4-targeted immunomodulators, such as MPLA, improve innate host resistance to infection in high risk subjects. Pre-clinical studies will establish the safety and efficacy of MPLA in large animal models of burn wound infection and post-burn pneumonia. Specific Aim 1: To define the cellular mechanisms by which MPLA augments innate antimicrobial functions. This aim will test the hypothesis that treatment with MPLA will improve the response to infection after burn injury by inducing G-CSF-mediated expansion of the bone marrow neutrophil pool and causing augmentation of neutrophil chemotaxis. Specific aim 2: To define intracellular signaling alterations by which MPLA augments resistance to infection. This aim will test the hypothesis that MPLA treatment will cause alterations in infection-induced signaling resulting in predominance of the protective PI3K and Trif/IRF-3/IFN¿ pathways. Specific Aim 3: To determine the safety and efficacy of MPLA in an ovine model of burn wound infection and post-burn pneumonia. This aim will test the hypothesis that MPLA will be well tolerated in burned sheep and will improve their response to wound infection and pneumonia. The results gained in the proposed studies will facilitate the translation of TLR4-targeted immunomodulators into the clinical setting and will fill important gaps in knowledge by advancing our understanding of the cellular and molecular mechanisms by which TLR-based immunomodulators improve host resistance to infections.

描述（由申请人提供）：大面积烧伤导致保护性皮肤屏障丧失和抗菌防御机制失调，导致烧伤伤口定植和细菌传播到血液、肺和其他组织的理想条件。虽然局部和全身抗生素是常规使用，脓毒症是延长住院时间和死亡的烧伤患者生存的最初的侮辱最常见的原因。脓毒症的频率和严重程度因抗生素耐药细菌的日益普遍而加剧。因此，需要新的治疗方法来提高严重烧伤患者对感染的抵抗力。我们的研究表明，用Toll样受体4（TLR 4）激动剂单磷酰脂质A（MPLA）治疗可有效改善小鼠对铜绿假单胞菌烧伤创面脓毒症的先天宿主抗性。MPLA具有低毒性，目前在临床环境中广泛用作疫苗佐剂。然而，MPLA增强宿主对全身性细菌感染的反应的机制尚未得到很好的理解，需要进一步的工作来将MPLA在高风险患者中的使用转化为临床环境。该项目的目标是确定TLR 4靶向免疫调节剂（如MPLA）改善高危受试者先天宿主对感染的抵抗力的细胞和分子机制。临床前研究将确定MPLA在烧伤伤口感染和烧伤后肺炎的大型动物模型中的安全性和有效性。具体目标1：确定MPLA增强先天抗菌功能的细胞机制。这一目的将测试的假设，即治疗MPLA将改善烧伤后感染的反应，诱导G-CSF介导的骨髓中性粒细胞池的扩张，并导致中性粒细胞趋化性增强。具体目标2：确定MPLA增强抗感染能力的细胞内信号转导改变。这一目的将检验以下假设：MPLA治疗将导致感染诱导的信号传导改变，导致保护性PI 3 K和Trif/IRF-3/IFN？途径占优势。具体目的3：确定MPLA在烧伤伤口感染和烧伤后肺炎的绵羊模型中的安全性和有效性。这一目标将检验MPLA在烧伤绵羊中具有良好耐受性的假设，并将改善它们对伤口感染和肺炎的反应。在拟定研究中获得的结果将有助于将TLR 4靶向免疫调节剂转化为临床环境，并将通过促进我们对基于TLR的免疫调节剂改善宿主对感染的抵抗力的细胞和分子机制的理解来填补重要的知识空白。