Targeting ACOD1 to attenuate innate immune responses to lethal infections

摘要 住院患者微生物感染的主要原因是革兰氏阴性菌，它们释放出 细胞壁成分脂多糖(LPS)，能够激活天然免疫途径。《乌头》 脱羧酶1(ACOD1)是一种内毒素诱导的线粒体酶，以前被认为是一种 负性先天免疫调节剂通过催化产生抗炎衣康酸。然而，我们 最近证明，内毒素诱导的ACOD1上调也具有强烈的促炎作用 单核细胞和巨噬细胞以衣康酸不依赖的方式作出反应。ACOD1基因缺失或 它的上游信号转导CDK2在髓系细胞或药物抑制CDK2(与地奈西利)一致 减少感染诱导的细胞因子风暴和临床前环境中的动物致死率。临床上，CDK2- ACOD1轴同样上调，并与细菌感染的严重程度呈正相关。 40名患者组成的队列。因此，我们的发现表明，ACOD1在促进失调中扮演了一个新的角色 对致命感染的先天免疫反应。我们的中心假设是ACOD1发挥促炎作用 通过与其他效应器(如GIMAP7)交互来执行操作。为了检验这一假设，我们将利用一个 多方面的战略，以追求以下综合目标。目标1：确定负责 CDK2介导的单核巨噬细胞ACOD1上调。目标2：确定负责的效应者 用于ACOD1介导的单核细胞和巨噬细胞的促炎细胞因子的产生。目标3：评估 抗癌药物阻断ACOD1/GIMAP7相互作用和对抗致死性感染的作用 临床前环境。这些研究的完成将对复杂的机制提供新的见解 潜在的感染诱导的先天免疫功能障碍和新疗法的开发 管理致命感染的战略。

ABSTRACT A leading cause of microbial infections in hospitalized patients is Gram-negative bacteria, which release the cell wall component lipopolysaccharide (LPS) capable of activating innate immune pathways. The aconitate decarboxylase 1 (ACOD1) is an LPS-inducible mitochondrial enzyme that was previously implicated as a negative innate immune regulator through catalyzing the production of anti-inflammatory itaconate. However, we recently demonstrated that the LPS-induced ACOD1 up-regulation also confers a robust pro-inflammation response in monocytes and macrophages in an itaconate-independent manner. Genetic deletion of ACOD1 or its upstream signaling CDK2 in myeloid cells or pharmacological inhibition of CDK2 (with dinaciclib) uniformly attenuated infection-induced cytokine storm and animal lethality in pre-clinical setting. Clinically, the CDK2- ACOD1 axis was similarly up-regulated and positively correlated with the severity of bacterial infections in a cohort of 40 patients. Thus, our findings have suggested a novel role for ACOD1 in promoting dysregulated innate immune responses to lethal infections. Our central hypothesis is that ACOD1 exerts pro-inflammatory action through interacting with other effectors such as GIMAP7. To test this hypothesis, we will exploit a multifaceted strategy to pursue the following integrated aims. Aim 1: Define the adaptor proteins responsible for CDK2-mediated ACOD1 upregulation in monocytes and macrophages. Aim 2: Identify the effectors responsible for ACOD1-mediated pro-inflammatory cytokine production in monocytes and macrophages. Aim 3: Evaluate the efficacy of anticancer drugs in disrupting ACOD1/GIMAP7 interaction and fighting against lethal infections in preclinical settings. The completion of these studies will provide new insights into the intricate mechanism underlying infection-induced innate immune dysfunction and shed light on the development of novel therapeutic strategy for the management of lethal infections.