Targeting ACOD1 to attenuate innate immune responses to lethal infections

摘要 住院患者中微生物感染的主要原因是革兰氏阴性菌，其释放 细胞壁组分脂多糖（LPS），能够激活先天免疫途径。乌头酸 脱羧酶1（ACOD 1）是一种LPS诱导的线粒体酶，以前被认为是一种 通过催化产生抗炎的衣康酸来抑制先天性免疫调节剂。但我们 最近证明，LPS诱导的ACOD 1上调也赋予了强大的促炎症作用， 在单核细胞和巨噬细胞中以衣康酸盐非依赖性方式应答。ACOD 1基因缺失或 其在骨髓细胞中上游信号传导CDK 2或对CDK 2的药理学抑制（使用dinaciclib）一致 在临床前环境中减弱感染诱导的细胞因子风暴和动物致死率。在临床上，CDK 2- ACOD 1轴也同样上调，并与细菌感染的严重程度呈正相关。 40名患者的队列。因此，我们的研究结果表明，ACOD 1在促进调节失调中的新作用， 对致命感染的先天免疫反应我们的中心假设是ACOD 1发挥促炎作用， 通过与其他效应器（如GIMAP 7）相互作用来执行操作。为了验证这一假设，我们将利用一个 这是一个多方面的战略，以实现以下综合目标。目的1：定义负责 单核细胞和巨噬细胞中CDK 2介导的ACOD 1上调。目标2：确定负责的效应者 单核细胞和巨噬细胞中ACOD 1介导的促炎细胞因子产生。目标3：评估 抗癌药物在破坏ACOD 1/GIMAP 7相互作用和对抗致命感染方面的功效， 临床前环境。这些研究的完成将为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，并揭示了新的治疗方法的发展 致命感染管理战略。

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.