The role of Immunoresponsive gene 1 in protection against infection

免疫反应基因 1 在预防感染中的作用

• 批准号: 10669658
• 负责人: Margaret Ann McBride
• 金额: $ 5.18万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669658
• 关键词: Aconitic Acid; Affect; Agonist; Antigens; Antimicrobial Resistance; Attenuated; Bacteria; Bacterial Infections; Biogenesis; Body Temperature; Bone Marrow; Cells; Cessation of life; Citric Acid Cycle; Clinical; Complex; Critical Illness; Data; Disease; Electron Transport; Enzymes; Exposure to; Generations; Genes; Glycolysis; Goals; Gram-Negative Bacterial Infections; Hospitals; Host resistance; Immunity; Immunologic Memory; In Vitro; Infection; Infection prevention; Injury to Kidney; Innate Immune System; Investigation; Knock-out; Knockout Mice; Knowledge; Laboratories; Ligands; Light; Lipid A; Lysosomes; Macrophage; Measures; Mediating; Medical Technology; Memory; Metabolic; Metabolism; Microbe; Mitochondria; Modeling; Molecular; Mycoses; Natural Immunity; Nosocomial Infections; Oxidative Phosphorylation; Pathway interactions; Patients; Phagocytosis; Phenotype; Physicians; Play; Production; Property; Prophylactic treatment; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Publishing; Reactive Oxygen Species; Recording of previous events; Research; Resistance to infection; Respiratory Burst; Role; Scientist; Small Interfering RNA; Staphylococcus aureus; Staphylococcus aureus infection; Succinate Dehydrogenase; TLR4 gene; Testing; Training; Translations; United States; Vaccine Adjuvant; Vaccines; Vacuole; Vulnerable Populations; antimicrobial; combat; cytokine; experimental study; first responder; improved; in vivo; infection management; innate immune mechanisms; insight; knock-down; liver injury; memory retention; microbial; pathogen; pathogen exposure; patient population; recruit; response

PROJECT SUMMARY/ABSTRACT Hospital acquired infections are a major problem in the United States, affecting approximately 2 million patients and causing at least 90,000 deaths ever year. New strategies are needed to combat these infections, especially in light of rising antimicrobial resistance rates among pathogens. Vaccines, one of the most impactful medical technologies in history, are based on adaptive immunological memory responses, which are long lasting and antigen specific. It is now known that cells of the innate immune system also can mount memory responses, but unlike adaptive memory responses, they provide protection against a broad variety of pathogens. This phenomenon is termed innate immune memory or trained immunity and is a potential solution for preventing infections in vulnerable populations. The mechanisms behind innate immune memory are not well understood. Toll-like receptor 4 ligands, including the vaccine adjuvant monophosphoryl lipid A (MPLA), induce innate immune memory in macrophages. MPLA treatment of macrophages causes metabolic reprogramming as well as increases antimicrobial functions in vitro. In vivo, it protects against Gram-positive bacterial, Gram-negative bacterial, and fungal infections. Our preliminary data shows that MPLA treatment induces high expression of Immunoresponsive gene 1 (Irg1), the enzyme which catalyzes production of itaconate, leading to improved bacterial clearance, an effect that is reduced in Irg1 knockout mice. Itaconate is known to alter metabolism through inhibition of succinate dehydrogenase. It is also an antimicrobial metabolite recently discovered to be delivered to bacteria-containing vacuoles. Based on these findings, we hypothesize that Irg1 and itaconate enable the generation of innate immune memory by facilitating macrophage metabolic reprogramming and augmenting lysosome-mediated antimicrobial functions. Aim 1 will determine the role of Irg1 in generation of the memory phenotype in vitro. Irg1 knockout bone marrow-derived macrophages (BMDM) will be studied to determine the contribution of Irg1 to the metabolic and functional changes associated with memory. Treatment with exogenous itaconate will be explored to determine its ability to induce innate immune memory separately from Irg1 activation. Aim 2 will explore the contributions of Irg1 to MPLA-induced protection against infection and disease tolerance in vivo. Knowledge of the mechanism of innate immune memory is critical to its translation to the clinical setting. This project will be undertaken as part of physician-scientist training through the Vanderbilt MSTP.

项目摘要/摘要 医院获得的感染是美国的主要问题，影响了约200万患者 每年至少造成90,000人死亡。需要新的策略来打击这些感染， 特别是鉴于病原体中抗菌素耐药率的上升。疫苗，最多的疫苗之一 历史上有影响力的医疗技术基于自适应免疫记忆反应，这是 特定于持久和抗原。现在众所周知，先天免疫系统的细胞也可以安装 记忆响应，但与自适应记忆反应不同，它们为广泛的各种各样的保护提供了保护 病原体。该现象称为先天免疫记忆或受过训练的免疫力，是潜在的解决方案 用于预防脆弱人群的感染。先天免疫记忆背后的机制不是 理解。 Toll样受体4配体，包括疫苗辅助单磷酸脂质A（MPLA）， 诱导巨噬细胞中的先天免疫记忆。 MPLA治疗巨噬细胞会导致代谢 重新编程并增加体外抗菌功能。在体内，它可以防止革兰氏阳性 细菌，革兰氏阴性细菌和真菌感染。我们的初步数据表明MPLA治疗 诱导免疫响应基因1（IRG1）的高表达，该酶催化产生的酶 Itaconate，导致细菌清除率提高，这种作用在IRG1敲除小鼠中降低。 Itaconate是 已知可以通过抑制琥珀酸脱氢酶来改变新陈代谢。它也是一种抗菌代谢物 最近被发现被输送到含细菌的液泡中。根据这些发现，我们假设 IRG1和Itaconate通过促进巨噬细胞可以产生先天免疫记忆 代谢重编程和增强溶酶体介导的抗菌功能。目标1意志 确定IRG1在体外生成记忆表型中的作用。 IRG1敲除骨髓衍生的 将研究巨噬细胞（BMDM），以确定IRG1对代谢和功能的贡献 与内存关联的更改。将探索用外源性岩岩处理以确定其能力 与IRG1激活分开诱导先天免疫记忆。 AIM 2将探讨IRG1对 MPLA诱导的防止感染和体内疾病耐受性的保护。了解机制 先天免疫记忆对于将其转化为临床环境至关重要。该项目将作为一部分进行 通过Vanderbilt MSTP进行医师科学家培训。