The role of Immunoresponsive gene 1 in protection against infection

项目总结/摘要 医院获得性感染是美国的一个主要问题，影响大约200万患者 每年至少造成9万人死亡需要新的战略来对抗这些感染， 特别是鉴于病原体中抗菌素耐药性的上升。疫苗是人类历史上 历史上最有影响力的医疗技术，都是基于适应性免疫记忆反应， 持久和抗原特异性。现在我们知道先天免疫系统的细胞也可以 记忆反应，但与适应性记忆反应不同，它们提供了对各种各样的记忆反应的保护。 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 来预防脆弱人群的感染。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，包括疫苗佐剂单磷酰脂质A（MPLA）， 诱导巨噬细胞先天免疫记忆。MPLA治疗巨噬细胞导致代谢性 重编程以及增加体外抗微生物功能。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。我们的初步数据显示，MPLA治疗 诱导免疫应答基因1（Irg 1）的高表达，Irg 1是一种催化 衣康酸，导致改善的细菌清除，这种作用在Irg 1敲除小鼠中降低。衣康酸是 已知通过抑制琥珀酸脱氢酶改变代谢。它也是一种抗菌代谢物 最近发现它被运送到含有细菌的空泡中。基于这些发现，我们假设 Irg 1和衣康酸盐通过促进巨噬细胞 代谢重编程和增强溶酶体介导的抗微生物功能。目标1将 确定Irg 1在体外记忆表型产生中的作用。Irg 1敲除骨髓源性 将研究巨噬细胞（BMDM），以确定Irg 1对代谢和功能的贡献。 与记忆有关的变化。将探索用外源性衣康酸盐治疗以确定其能力 诱导先天免疫记忆与Irg 1激活分开。目标2将探讨Irg 1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。了解的机制 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 通过范德比尔特MSTP进行的医学科学家培训。

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.