Metabolism, infection and immunity in inborn errors of metabolism

先天性代谢缺陷中的代谢、感染和免疫

• 批准号: 8948396
• 负责人: Peter McGuire
• 金额: $ 86.38万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8948396
• 关键词: Accounting; Acute; Acyl CoA Dehydrogenases; Address; Affect; Amino Acids; Animal Model; Animals; Area; Arginine; Attention; B-Lymphocytes; Biochemical; Biological Models; CD19 gene; Carnitine; Cell physiology; Cells; Cerebrum; Clinical; Clinical Protocols; Collaborations; Critical Care; Data; Defect; Deterioration; Disease; Electron Transport; Energy Metabolism; Enzymes; Equilibrium; Evaluation; Failure; Flavoproteins; Functional disorder; Goals; Hepatic; Human; Hyperammonemia; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunology; Inborn Errors of Metabolism; Infection; Inflammatory; Influenza; Intervention; Investigation; Laboratories; Life; Life Experience; Liver; Liver diseases; Lymphocyte; Lymphocyte Function; Manuscripts; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial Diseases; Modeling; Morbidity - disease rate; Mus; Nitrogen; Organ; Patients; Physiological; Poly I-C; Preparation; Protocols documentation; Pyruvate; Recovery; Recruitment Activity; Research; Respiratory Chain; Role; Sepsis; Study models; Supplementation; Syndrome; T cell differentiation; T-Lymphocyte; Testing; Texas; Therapeutic Intervention; Tissues; Translational Research; United States National Institutes of Health; Universities; Viremia; Wild Type Mouse; acyl-CoA dehydrogenase; argininosuccinate synthase; body system; complex IV; enzyme deficiency; fatty acid oxidation; immune activation; immune function; improved; insight; long chain fatty acid; macrophage; metabolic abnormality assessment; metabolomics; mitochondrial dysfunction; mouse model; neuropathology; nitrogen metabolism; patient population; programs; simulation; urea cycle

Summary: Our translational research program focuses on immunometabolism using inborn errors of metabolism (IEM) as a model system to examine the interaction between metabolism and immune activation. Using IEM as a model system is a unique approach to studying immunometabolism. Patients with IEM experience life-threatening episodes of acute metabolic instability and organ dysfunction due to infection. Our goal is to understand how immune activation during infection contributes to this pathophysiology. This research also has implications for organ dysfunction during sepsis, a common problem in critical care. Since infection is important in patients with IEM, we also wish to understand the role of metabolism in lymphocyte function. Many enzymes involved in metabolism are expressed in lymphocytes, and have associated IEM. These studies will not only provide insight into immune function in IEM patients, but also help define the role of various metabolic enzymes in lymphocyte function. Specifically, our aims are: 1) To understand the effects of immune system activation on organ metabolism. 2) To understand the role of intermediary metabolism in immune cell function. Research: 1) The effects of immune system activation on organ metabolism. Acute metabolic decompensation in IEM is characterized by rapid onset deterioration in metabolic status leading to life threatening biochemical perturbations (e.g. hyperammonemia). Infection is the major cause of acute metabolic decompensation in patients with IEM. For example, in patients with urea cycle disorders (UCD), a disorder of hepatic amino acid metabolism, infection causes acute life-threatening hyperammonemia and is associated with increased morbidity (McGuire et al, J Peds, 2013). We postulated that activation of the immune system during infection accounted for this increased morbidity. To address the effects of immune activation on organ metabolism, we established a model system of acute metabolic decompensation due to influenza infection using a mouse model of UCD (McGuire et al, Dis Model Mech, 2014). Via this model, we described some of the mechanisms involved in precipitating hyperammonemia, including inhibition of mitochondrial urea cycle enzymes and depletion of urea cycle intermediates in the liver. These findings suggest that supplementation with urea cycle intermediates during infection may be beneficial for UCD patients. Perturbations in amino acid metabolism in UCD due to infection may also extend beyond the liver. Cerebral amino acid depletion can also be seen during systemic immune activation and may account for the neuropathology seen in UCD during infection (Tarasenko et al, in review). From these animal studies of altered amino acid metabolism, we have developed mathematical simulations of whole body nitrogen metabolism in humans during infection. The model allows us to test therapeutic interventions for restoring nitrogen (and amino acid) balance during infection, a major problem in many IEM (manuscript in preparation). In our infection model above, we see hepatic metabolic perturbations in wild-type (WT) mice. These data led us to suggest that acute metabolic decompensation in IEM may represent a failure to adapt to normal physiologic mechanisms during infection. To answer this question, we used a metabolomic approach to identify hepatic metabolic pathways that may be impacted by immune activation in WT mice (manuscript in preparation). Using the same influenza infection model above, long chain fatty acids were identified as the most significantly changed metabolites. Defects at numerous steps in long chain fatty acid oxidation including the carnitine cycle, acyl-CoA dehydrogenases, and the electron transport flavoprotein were found. These data predict that patients with fatty acid oxidation disorders receive an additional metabolic insult during infection. Since the effects described aboove involve mitochondrial metabolism, we asked about the effects of immune activation on mitochondrial energy metabolism. Using a model system of viremia, (Poly I:C), we have demonstrated perturbations in hepatic pyruvate and respiratory chain metabolism in WT mice (manuscript in preparation). Importantly, these perturbations can be improved by depleting tissue macrophages. Moving forward, our immunometabolism studies are concentrating on hepatic mitochondrial metabolism and its adaptation to and recovery from inflammatory insults. Many IEM have mitochondrial dysfunction at baseline. In addition, we chose this strategy due to its broad application to other disease states such as multi-organ system dysfunction syndrome (MODS) due to sepsis. MODS involves mitochondrial dysfunction. We anticipate that our model system will serve as a platform for the evaluation of various interventions aimed at alleviating mitochondrial metabolic dysfunction. The role of intermediary metabolism in immune cell function. Since infection has serious consequences for patients with IEM, and to describe the interactions between intermediary metabolism and immune function, we developed a clinical protocol in the NIH Clinical Center in 2013, The NIH MINI Study: Metabolism Infection and Immunity in IEM (NCT01780168). This protocol is the first organized effort to examine immune function in IEM and is being performed with the Center for Human Immunology at NIH. To date, we have recruited over 45 patients with IEM and are identifying immune perturbations in organic acidemias, fatty acid oxidation defects, and mitochondrial diseases. Moving forward, we are focusing on IEM where cell intrinsic defects are expected, i.e. mitochondrial enzyme deficiencies. We initiated this line of investigation after identifying patients with disorders of mitochondrial metabolism and immune dysfunction. In collaboration with Drs. Susan Pacheco and Mary Kay Koenig at the University of Texas, Houston, we are evaluating immune function in a large population of patients with mitochondrial disease at the NIH Clinical Center. Immune cells undergo great changes in metabolism for proliferation and differentiation. This area of immunometabolism has recently seen a resurgence, however, using IEM as a translational model for understanding immune cell metabolism is unique. Initial studies in the laboratory helped define the role of arginine metabolism in T-cells. Using a mouse model of argininosuccinate synthetase (ASS1) deficiency, we were able to demonstrate the role of this enzyme, which is involved in arginine synthesis, in T-cell differentiation and function (Tarasenko et al., in review). In keeping with our clinical observations and focus, we have developed animal models to address the role of mitochondrial energy metabolism in immune cell function. To induce complex IV deficiency (COX10flox mice), T-lymphocytes and B-lymphocytes are being targeted using CD4-Cre and CD19-Cre respectively. The B-cell specific COX10 deficient mice have recently been produced and display abnormal immune responses, similar to our findings in patients. We will continue to characterize these mice and seek to develop interventions aimed at improving B-cell function.

摘要：我们的转化研究计划着重于使用代谢的先天错误（IEM）作为模型系统，以检查代谢与免疫激活之间的相互作用。使用IEM作为模型系统是研究免疫代谢的独特方法。 IEM患者经历了威胁生命的急性代谢不稳定性和器官功能障碍的发作。我们的目标是了解感染过程中的免疫激活如何有助于这种病理生理学。这项研究对败血症期间的器官功能障碍也具有影响，这是重症监护中的常见问题。由于感染在IEM患者中很重要，因此我们也希望了解代谢在淋巴细胞功能中的作用。许多参与新陈代谢的酶在淋巴细胞中表达，并与IEM相关。这些研究不仅可以洞悉IEM患者的免疫功能，还有助于定义各种代谢酶在淋巴细胞功能中的作用。 具体来说，我们的目标是： 1）了解免疫系统激活对器官代谢的影响。 2）了解中间代谢在免疫细胞功能中的作用。 研究： 1）免疫系统激活对器官代谢的影响。 IEM中的急性代谢代谢代谢的特征是代谢状态的快速发作恶化，导致生命威胁生命的生化扰动（例如高症血症）。感染是IEM患者急性代谢失代偿作用的主要原因。例如，在尿素周期疾病（UCD）的患者中，一种肝氨基酸代谢疾病，感染会引起急性威胁生命的高症血症，并与发病率升高有关（McGuire等，J Peds，2013）。我们假设感染期间免疫系统的激活造成了这种发病率的增加。为了解决免疫激活对器官代谢的影响，我们使用UCD的小鼠模型建立了由于流感感染引起的急性代谢代谢失代偿模型模型（McGuire等，Dis Model Mech，2014）。通过该模型，我们描述了沉淀高症血症的一些机制，包括抑制线粒体尿素周期酶和肝脏中尿素周期中间体的耗竭。这些发现表明，在感染过程中补充尿素周期中间体可能对UCD患者有益。由于感染引起的UCD氨基酸代谢的扰动也可能延伸到肝脏之外。 在全身免疫激活期间也可以看到脑氨基酸的耗竭，并且可能解释了感染过程中UCD中看到的神经病理学（Tarasenko等人，在综述中）。 从这些动物对氨基酸代谢改变的动物研究中，我们在感染过程中对人类的全身氮代谢进行了数学模拟。该模型使我们能够测试治疗干预措施，以恢复感染过程中氮（和氨基酸）平衡，这是许多IEM（手稿制备）的主要问题。 在上面的感染模型中，我们看到野生型（WT）小鼠中的肝代谢扰动。这些数据导致我们提出IEM中的急性代谢代谢代谢代谢可能未能适应感染期间正常的生理机制。为了回答这个问题，我们使用了代谢组方法来识别WT小鼠免疫激活可能影响的肝代谢途径（手稿中的手稿）。使用上面相同的流感感染模型，长链脂肪酸被确定为最显着变化的代谢产物。在长链脂肪酸氧化中的许多步骤中存在缺陷，包括肉碱循环，酰基-COA脱氢酶和电子转运黄蛋蛋白。这些数据预测，脂肪酸氧化障碍患者在感染期间会受到额外的代谢侮辱。 由于所描述的伴奏涉及线粒体代谢，因此我们询问了免疫激活对线粒体能量代谢的影响。使用病毒血症的模型系统（Poly I：C），我们在WT小鼠的肝丙酮酸和呼吸链代谢中表现出扰动（手稿）。重要的是，可以通过耗尽组织巨噬细胞来改善这些扰动。向前迈进，我们的免疫代谢研究集中在肝线粒体代谢及其对炎症性损伤中的适应和恢复。许多IEM在基线时具有线粒体功能障碍。此外，由于其广泛应用于其他疾病状态，例如由于败血症而引起的多器官系统功能障碍综合征（MOD），因此我们选择了该策略。 mods涉及线粒体功能障碍。我们预计我们的模型系统将成为评估旨在减轻线粒体代谢功能障碍的各种干预措施的平台。 中间代谢在免疫细胞功能中的作用。由于感染对IEM患者产生了严重的影响，并描述了中介代谢和免疫功能之间的相互作用，因此我们于2013年在NIH临床中心开发了临床方案，NIH MINI研究：IEM代谢感染和免疫力（NCT01780168）。该方案是检查IEM中免疫功能的首次有组织的努力，并正在NIH的人类免疫学中心进行。迄今为止，我们已经招募了45例IEM患者，并且正在鉴定有机酸性，脂肪酸氧化缺陷和线粒体疾病中的免疫扰动。向前迈进，我们将重点放在预期细胞内在缺陷的IEM上，即线粒体酶缺陷。在鉴定出有线粒体代谢和免疫功能障碍的患者之后，我们开始了这一研究。与Drs合作。休斯敦德克萨斯大学的苏珊·帕切科（Susan Pacheco）和玛丽·凯·科尼格（Mary Kay Koenig）我们正在评估NIH临床中心大量线粒体疾病患者的免疫功能。 免疫细胞在代谢中发生了巨大变化，以进行增殖和分化。然而，这种免疫代谢区域最近看到了一种复兴，使用IEM作为理解免疫细胞代谢的转化模型是独一无二的。实验室的初步研究有助于定义精氨酸代谢在T细胞中的作用。使用精氨酸合成酶（ASS1）缺乏的小鼠模型，我们能够证明该酶在T细胞分化和功能中所涉及的酶的作用（Tarasenko等人，在综述中）。为了与我们的临床观察和重点保持一致，我们开发了动物模型，以解决线粒体能量代谢在免疫细胞功能中的作用。为了诱导复杂的IV缺乏（Cox10flox小鼠），使用CD4-CRE和CD19-CRE分别针对T淋巴细胞和B淋巴细胞。最近已经产生了B细胞特异性COX10缺乏小鼠并显示出异常的免疫反应，类似于我们的患者发现。我们将继续描述这些小鼠，并寻求制定旨在改善B细胞功能的干预措施。