Macrophage mitochodrial reprogramming and innate immune memory

巨噬细胞线粒体重编程和先天免疫记忆

• 批准号: 10333362
• 负责人: EDWARD R SHERWOOD
• 金额: $ 42.5万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-13 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10333362
• 关键词: Aconitic Acid; Adaptive Immune System; Affect; Agonist; American; Antimicrobial Effect; Automobile Driving; Biogenesis; Biology; Burn Trauma; Cause of Death; Cell Respiration; Cell physiology; Cells; Cessation of life; Citric Acid; Citric Acid Cycle; Clinical; Complication; Critical Illness; Development; FRAP1 gene; Foundations; Genes; Glycolysis; Goals; Healthcare Systems; Hospitals; Immune; Immune response; Immunologic Memory; Immunotherapy; Incidence; Individual; Infection; Innate Immune Response; Innate Immune System; Knockout Mice; Knowledge; Leukocytes; Ligands; Lipid A; Memory; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Myeloid Cells; Nosocomial Infections; Organism; Oxidative Phosphorylation; Pathway interactions; Patients; Peptidoglycan; Phenotype; Play; Production; Pseudomonas aeruginosa; Public Health; Resistance; Resistance to infection; Role; Sepsis; Severities; Signal Pathway; Signal Transduction; Staphylococcus aureus infection; TLR4 gene; Testing; Vaccines; Vulnerable Populations; antimicrobial; base; beta-Glucans; clinically relevant; cognitive disability; cytokine; gene product; high risk; immune resistance; immune system function; in vivo; macrophage; metabolic phenotype; microbial; mitochondrial metabolism; mortality; organ injury; pathogen; pathogen exposure; pathogenic bacteria; pathogenic fungus; physically handicapped; prevent; recruit; response; severe burns; surgical risk

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.

项目摘要 医院可获得的感染是对公共卫生的主要威胁，影响了200万患者并引起 每年至少有90,000人死亡。败血症是医院获得感染患者的常见并发症 以及非心脏重症监护病房（ICU）中死亡的主要原因。尝试治疗医院的尝试 事实证明，感染和败血症非常困难，生存的败血症患者长期遭受 身体和认知障碍以及高1年死亡率。因此，需要新的策略 减少了医院获得的感染和败血症的燃烧。旨在诱导的免疫疗法 先天免疫记忆提供了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，并可以引起坚固的，广谱的记忆 对随后感染的抗菌反应。用TLR4配体的治疗，例如单磷酸脂质A （MPLA），承认先天的免疫记忆和对广泛临床上重要病原体的抵抗力 持续超过2周。我们建议基于TLR4配体的适当应用 免疫疗法诱导先天免疫记忆具有减少燃烧的巨大潜力 医院获得的感染和败血症。巨噬细胞是天生发展的基础 免疫记忆。最近的证据表明，巨噬细胞代谢的重塑对于 诱导先天免疫记忆。用TLR4配体启动诱导巨噬细胞代谢表型 以糖酵解，氧化代谢和线粒体生物发生的增加为特征 免疫响应基因1（IRG1）表达和Itaconate的酸性循环通量和相关的增加 生产。我们假设巨噬细胞代谢重塑和增加的产生 IRG1和Itaconate对于产生先天免疫记忆至关重要。为了定义潜在的生物学， 我们将：（1）。确定IRG1和ITACONATE驱动TLR4激动剂诱导的先天免疫记忆 巨噬细胞； （2）。将IRG1，Itaconate和NRF2的重要性定义为主机响应的调节剂 在体内TLR4激动剂治疗后，常见医院获得的病原体感染； （3）。定义 细胞内信号通路驱动线粒体生物发生，IRG1表达和Itaconate的产生 TLR4激动剂绘制的巨噬细胞； （4）。确定潜水员微生物配体诱导的能力 巨噬细胞线粒体生物发生，重编程线粒体代谢和功能并诱导先天 免疫记忆。我们将检验以下假设：像TLR4激动剂一样，微生物配体（例如辣椒果）， CpG ODN和β-葡聚糖具有重新编程巨噬细胞代谢并诱导记忆的能力 以线粒体生物发生的特征，柠檬酸周期通量增加的表型，IRG1增加 与抗菌功能的相关增强的表达和Itaconate产生。