The effect of MPLA treatment on immune responses to infection after severe burn

MPLA治疗对严重烧伤后感染免疫反应的影响

基本信息

批准号：
8647455
负责人：
Julia K. Bohannon
金额：
$ 5.33万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8647455
关键词：
Adverse effects Aftercare Agonist Antibiotic Resistance Antimicrobial Effect Area Attenuated Bacteria Bone Marrow Burn injury CSF3 gene Cause of Death Cell Adhesion Molecules Cells Clinical Data Dose Endotoxins Immune Immune response Immunity Immunocompromised Host Immunology Immunomodulators Infection Infection Control Inflammatory Injury Knowledge Lead Lipopolysaccharides Mediating Multiple Organ Failure Mus Neutrophil Infiltration Opportunistic Infections Patients Production Property Pseudomonas aeruginosa Research Research Training Resistance Resistance to infection Role Sepsis Signal Pathway Signal Transduction Site Skin Staging Testing Training Trauma Wound Infection antimicrobial base career cytokine design fMet-Leu-Phe receptor immune function improved injured monophosphoryl lipid A mouse model neutrophil pathogenic bacteria prevent public health relevance research study response skills toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): As a result of loss of the protective barrier of the skin combined with numerous injury-induced immunological alterations that decrease the ability to clear and control infections, severely burned patients are highly susceptible to opportunistic infections. Infection remains the leading cause of death in patients that survive the initial burn injury. Toll-like receptor 4 agonists lipopolysaccharide (LPS) and monophosphoryl lipid A (MPLA) have been shown to have strong immunomodulatory properties. Prior sensitization with low doses of LPS or MPLA is known to induce a state of tolerance to subsequent LPS challenge, which is associated with an enhanced ability to clear bacteria following systemic challenge with Pseudomonas aeruginosa. Whereas LPS has numerous undesirable side effects, MPLA is relatively innocuous and would therefore be more suited for clinical usage to enhance immune responses to infection. Previous studies have shown that treatment of mice with MPLA greatly enhances bacterial clearance after a burn wound infection, leading to increased survival and this clearance is mediated, in part, by increased recruitment of neutrophils to the site of infection. This proposal is designed to test the hypothesis that treatment of burn injured mice with MPLA will result in improved resistance to infection mediated by enhanced antimicrobial immunity, both locally and systemically. Using a mouse model of burn injury and associated infection to test this hypothesis, the following specific aims are proposed: Aim 1: To define the cellular mechanisms responsible for MPLA-mediated augmentation of innate antimicrobial responses after burn injury. This aim will test the sub-hypothesis that MPLA treatment will enhance neutrophil-mediated immune responses to a burn-associated infection. Aim 2: To determine the role of TLR4 signaling pathways in facilitating the antimicrobial effects of MPLA. This aim will test the sub-hypothesis that MPLA-enhancement of neutrophil-mediated antimicrobial responses and improvement in bacterial clearance is dependent upon TLR4- and Trif-mediated activation of the PI3K signaling pathway.

描述（由申请人提供）：由于皮肤保护屏障的丧失，加上许多损伤引起的免疫学改变，降低了清除和控制感染的能力，严重烧伤患者非常容易受到机会性感染。感染仍然是初次烧伤后幸存患者死亡的主要原因。 Toll 样受体 4 激动剂脂多糖 (LPS) 和单磷酰脂质 A (MPLA) 已被证明具有很强的免疫调节特性。已知先前用低剂量 LPS 或 MPLA 致敏可诱导对随后的 LPS 攻击的耐受状态，这与铜绿假单胞菌全身攻击后清除细菌的能力增强有关。 LPS 有许多不良副作用，而 MPLA 相对无害，因此更适合临床使用，以增强对感染的免疫反应。先前的研究表明，用 MPLA 治疗小鼠可以大大增强烧伤伤口感染后的细菌清除率，从而提高存活率，并且这种清除在一定程度上是通过增加中性粒细胞向感染部位的募集来介导的。该提案旨在检验以下假设：用 MPLA 治疗烧伤小鼠将提高局部和全身抗菌免疫力介导的感染抵抗力。使用烧伤和相关感染的小鼠模型来检验这一假设，提出以下具体目标：目标 1：确定烧伤后 MPLA 介导的先天抗菌反应增强的细胞机制。这一目标将检验 MPLA 治疗将增强中性粒细胞介导的对烧伤相关感染的免疫反应的子假设。目标 2：确定 TLR4 信号通路在促进 MPLA 抗菌作用中的作用。该目标将检验以下子假设：MPLA 增强中性粒细胞介导的抗菌反应和改善细菌清除取决于 TLR4 和 Trif 介导的 PI3K 信号通路激活。