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

描述(由申请人提供)：由于皮肤保护性屏障的丧失，加上许多由损伤引起的免疫变化，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。感染仍然是最初烧伤后幸存下来的患者的主要死亡原因。Toll样受体4激动剂脂多糖和单磷脂A具有很强的免疫调节作用。已知的是，预先用低剂量的内毒素或MPLA致敏可以诱导对随后的内毒素攻击的耐受状态，这与铜绿假单胞菌全身攻击后清除细菌的能力增强有关。尽管内毒素有许多不良副作用，但多聚乳酸相对无害，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，在烧伤创面感染后，用Mpla治疗小鼠可以极大地提高细菌的清除，从而增加存活率，这种清除在一定程度上是通过增加中性粒细胞对感染部位的募集而实现的。这一建议旨在检验这样一种假设，即烧伤小鼠使用Mpla治疗将通过增强局部和全身的抗微生物免疫来提高对感染的抵抗力。利用烧伤和相关感染的小鼠模型来验证这一假说，提出了以下具体目标：目的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免疫反应对烧伤相关感染的亚假说。目的：探讨TLR4信号通路在Mpla抗菌作用中的作用。这一目标将检验MLA增强中性粒细胞介导的抗菌反应和改善细菌清除依赖于TLR4和Trif介导的PI3K信号通路激活的亚假说。

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.