The role of Immunoresponsive gene 1 in protection against infection

项目摘要/摘要 医院获得性感染是美国的一个主要问题，影响到大约200万名患者 每年造成至少9万人死亡。需要新的战略来抗击这些感染， 特别是在病原体的抗菌素耐药率不断上升的情况下。疫苗，最多的疫苗之一 历史上有影响力的医疗技术是基于适应性免疫记忆反应的，这是 持久且具有抗原特异性。现在已经知道，先天免疫系统的细胞也可以 记忆反应，但与自适应记忆反应不同，它们提供了对各种 病原体。这种现象被称为先天免疫记忆或训练免疫，是一种潜在的解决方案 预防易受感染人群的感染。先天免疫记忆背后的机制并不是 很好理解。Toll样受体4配体，包括疫苗佐剂单磷脂A(MPLA)， 诱导巨噬细胞的天然免疫记忆。Mpla治疗巨噬细胞引起代谢 重新编程以及增加体外抗菌功能。在体内，它可以预防革兰氏阳性 细菌、革兰氏阴性细菌和真菌感染。我们的初步数据显示，Mpla治疗 诱导免疫反应基因1(IRG1)的高表达，IRG1是催化产生 衣康酸，导致改善细菌清除，这种影响在IRG1基因敲除小鼠中减弱。伊塔科特是 已知通过抑制琥珀酸脱氢酶来改变新陈代谢。它也是一种抗微生物代谢物。 最近被发现被输送到含有细菌的液泡中。基于这些发现，我们假设 IRG1和衣康酸通过促进巨噬细胞产生天然免疫记忆 代谢重新编程和增强溶酶体介导抗菌功能。目标1将 确定IRG1在体外记忆表型生成中的作用。IRG1基因敲除骨髓来源 巨噬细胞(BMDM)将被研究以确定IRG1对代谢和功能的贡献 与内存相关的更改。将探索外源性衣康酸的治疗方法，以确定其能力 诱导先天免疫记忆独立于IRG1激活。目标2将探讨IRG1对以下方面的贡献 Mpla诱导的体内抗感染和疾病耐受性保护作用。对致病机理的认识 先天免疫记忆是将其转化为临床环境的关键。该项目将作为 通过范德比尔特MSTP进行的内科科学家培训。

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.