Macrophage mitochodrial reprogramming and innate immune memory

项目摘要 医院获得性感染是对公共卫生的主要威胁，影响到200万患者，并导致 每年至少有9万人死亡。脓毒症是医院获得性感染患者的常见并发症。 也是非心脏重症监护病房(ICU)的主要死亡原因。治疗医院获得性疾病的尝试 感染和败血症已被证明是极其困难的，而存活下来的脓毒症患者将遭受长期的痛苦。 身体和认知残疾，一年死亡率高。因此，需要新的战略来 减少医院获得性感染和败血症的负担。免疫疗法旨在诱导 先天免疫记忆提供了一种实现这一目标的方法。最近的研究表明，先天免疫 细胞可以保留对先前病原体暴露的记忆，并被准备好引发一种强大的、广谱的 对后续感染的抗微生物反应。TLR4配体的治疗，如单磷酰脂A (Mpla)，赋予先天免疫记忆和对一系列临床重要病原体的抵抗力 持续两周以上。我们建议以TLR4为配体的适当应用 诱导先天免疫记忆的免疫疗法具有显著的潜力，可以减轻 医院获得性感染和败血症。巨噬细胞是先天发育的基础 免疫记忆。最近的证据表明，巨噬细胞代谢的重塑是 诱导先天免疫记忆。TLR4配体诱导巨噬细胞代谢表型 特点是随着柠檬酸的增加，糖酵解、氧化代谢和线粒体生物合成增加 酸循环通量和免疫反应基因1(IRG1)表达和衣康酸的相关增加 制作。我们假设巨噬细胞代谢重塑和增加的 IRG1和衣康酸是产生先天免疫记忆所必需的。为了定义潜在的生物学， 我们将：(1)。确定IRG1和衣康酸如何驱动TLR4激动剂诱导的先天性免疫记忆 巨噬细胞；确定IRG1、衣康酸和Nrf2作为宿主反应的调节因子的重要性 体内TLR4激动剂治疗后常见医院获得性病原菌感染情况。定义 线粒体生物发生、IRG1表达和衣康酸产生的细胞内信号通路 TLR4激动剂诱导的巨噬细胞；确定不同微生物配体诱导的能力 巨噬细胞线粒体生物发生，重新编程线粒体代谢和功能并诱导先天 免疫记忆。我们将检验这一假设，就像TLR4激动剂一样，微生物配体如肽聚糖， CpG ODN和β-葡聚糖具有重新编程巨噬细胞代谢和诱导记忆的能力 以线粒体生物发生为特征的表型，柠檬酸循环通量增加，IRG1增加 表达和衣康酸生产与相关的抗菌功能的增强。

Project Summary Hospital-acquired infections are a major threat to public health, impacting 2 million patients and causing at least 90,000 deaths annually. Sepsis is a common complication in patients with hospital-acquired infections and the leading cause of death in non-cardiac intensive care units (ICU). Attempts at treating hospital-acquired infections and sepsis have proven exceedingly difficult and patients that survive sepsis suffer long-term physical and cognitive disabilities and a high 1-year mortality rate. Therefore, new strategies are needed to decrease the burden of hospital-acquired infections and sepsis. Immunotherapy aimed at inducing innate immune memory provides a way of achieving that goal. Recent studies show that innate immune cells can retain memory of prior pathogen exposure and are primed to elicit a robust, broad-spectrum antimicrobial response to subsequent infection. Treatment with TLR4 ligands, such as monophosphoryl lipid A (MPLA), confers innate immune memory and resistance to a broad array of clinically important pathogens that persists for more than 2 weeks. We propose that the appropriate application of TLR4 ligand-based immunotherapy to induce innate immune memory has significant potential to reduce the burden of hospital-acquired infections and sepsis. Macrophages are the foundation for development of innate immune memory. Recent evidence indicates that remodeling of macrophage metabolism is central to the induction of innate immune memory. Priming with TLR4 ligands induces a macrophage metabolic phenotype characterized by increased glycolysis, oxidative metabolism and mitochondrial biogenesis with increased citric acid cycle flux and associated increases in immunoresponsive gene 1 (Irg1) expression and itaconate production. We hypothesize that macrophage metabolic remodeling and the increased production of Irg1 and itaconate are essential to generating innate immune memory. To define the underlying biology, we will: (1). Determine how Irg1 and itaconate drive TLR4 agonist-induced innate immune memory in macrophages; (2). Define the importance of Irg1, itaconate and Nrf2 as regulators of the host response to infection with common hospital-acquired pathogens after TLR4 agonist treatment in vivo.; (3). Define the intracellular signaling pathways driving mitochondrial biogenesis, Irg1 expression and itaconate production in TLR4 agonist-primed macrophages; (4). Determine the ability of diverse microbial ligands to induce macrophage mitochondrial biogenesis, reprogram mitochondrial metabolism and function and induce innate immune memory. We will test the hypothesis that, like TLR4 agonists, microbial ligands such as peptidoglycan, CpG ODN and β-glucan, have the ability to reprogram macrophage metabolism and induce a memory phenotype characterized by mitochondrial biogenesis, increased citric acid cycle flux, increased Irg1 expression and itaconate production with associated enhancement of antimicrobial functions.