Targeting ACOD1 to attenuate innate immune responses to lethal infections

靶向 ACOD1 减弱对致命感染的先天免疫反应

基本信息

批准号：
10729154
负责人：
Daolin Tang
金额：
$ 33.62万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10729154
关键词：
Aconitic Acid Adaptor Signaling Protein Animals Anti-Inflammatory Agents Antineoplastic Agents Attenuated Automobile Driving Bacterial Infections Binding Biochemistry Biological Response Modifiers CDK2 gene Carbon Carboxy-Lyases Cell Wall Cells Clinical Communicable Diseases Complex Development Dinucleoside Phosphates Drug Screening Enzymes Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Genes Genetic Genetic Transcription Gram-Negative Bacteria Guanosine Triphosphate Phosphohydrolases Hospitalization Immune System Diseases Immune system Immunity Infection Inflammation Inflammatory Inflammatory Response Innate Immune Response Lipopolysaccharides Macrophage Mediating Mediator Metabolism Mitochondria Multiple Organ Failure Mus Myeloid Cells Natural Immunity Non-Small-Cell Lung Carcinoma Pathway interactions Patients Periodicity Phosphorylation Positioning Attribute Production Proteins Research Role Safety Severities Signal Pathway Signal Transduction Stimulus TNF gene Testing Transgenic Animals Up-Regulation cohort cytokine cytokine release syndrome efficacy evaluation fighting gain of function mutation improved infectious disease treatment inhibitor innate immune pathways insight jun Oncogene microbial monocyte new therapeutic target next generation sequencing novel novel therapeutic intervention pharmacologic pre-clinical prevent protein complex response therapeutic target transcription factor

项目摘要

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.

抽象的住院患者微生物感染的主要原因是革兰氏阴性菌，它释放出细胞壁成分脂多糖（LPS）能够激活先天免疫途径。乌头酸脱羧酶 1 (ACOD1) 是一种 LPS 诱导型线粒体酶，之前被认为是一种通过催化抗炎衣康酸的产生来调节先天性免疫负调节剂。然而，我们最近证明，LPS 诱导的 ACOD1 上调也具有强大的促炎症作用单核细胞和巨噬细胞以不依赖衣康酸的方式做出反应。 ACOD1 基因缺失或其在骨髓细胞中的上游信号传导 CDK2 或统一抑制 CDK2（使用 dinaciclib）在临床前环境中减轻感染引起的细胞因子风暴和动物致死率。临床上，CDK2- ACOD1 轴同样上调，并且与细菌感染的严重程度呈正相关。队列由 40 名患者组成。因此，我们的研究结果表明 ACOD1 在促进失调方面具有新的作用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（例如 GIMAP7）交互来采取行动。为了检验这个假设，我们将利用多方面的战略，以实现以下综合目标。目标 1：定义负责的接头蛋白 CDK2 介导的单核细胞和巨噬细胞中 ACOD1 上调。目标 2：确定负责的效应器用于单核细胞和巨噬细胞中 ACOD1 介导的促炎细胞因子的产生。目标 3：评估抗癌药物在破坏 ACOD1/GIMAP7 相互作用和对抗致命感染方面的功效临床前设置。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引起的先天免疫功能障碍，并为新型治疗方法的开发提供了线索致命感染的管理策略。