Metabolic approaches to treat severe viral and inflammatory diseases

治疗严重病毒性疾病和炎症性疾病的代谢方法

基本信息

批准号：
8554692
负责人：
AUGUSTO C. OCHOA
金额：
$ 50.71万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-25 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8554692
关键词：
Acute Pneumonia Adenoviruses Adrenal Cortex Hormones Adult Respiratory Distress Syndrome Adverse effects Amino Acids Animals Antiviral Agents Arginine Asparagine Blindness Cessation of life Chronic Clinic Complication Cornea Data Dendritic Cells Developed Countries Development Disease Disease model Dose Drug Targeting Encephalitis Ensure Enzymes Growth Healed Herpes Simplex Infections Herpes encephalitis Herpesviridae Herpesvirus 1 Human Human Herpesvirus 2 Immune response Immune system Immunity In Vitro Infection Infection Control Infection prevention Inflammation Inflammatory Inflammatory Response Influenza Keratitis Keratoconjunctivitis Latent Virus Lead Malignant Childhood Neoplasm Mediating Mental Retardation Metabolic Metabolic Pathway Molecular Molecular Target Mus Myelogenous Myeloid Cells Non-Essential Amino Acid Normal tissue morphology Oryctolagus cuniculus Papovaviridae Pathway interactions Pharmaceutical Preparations Phase I Clinical Trials Process Publishing Research Respiratory distress Satellite Viruses Severe Acute Respiratory Syndrome Steroids Suppressor-Effector T-Lymphocytes T-Cell Leukemia T-Lymphocyte Testing Therapeutic Therapeutic Effect Time Tissues Toxic effect Translating Tryptophan Tryptophan 2,3 Dioxygenase Tumor Escape Tumor Immunity Vaccines Viral Virus Virus Diseases West Nile virus Wound Healing arginase asparaginase cytokine disability drug development efficacy testing healing in vivo innovation neonate neovascularization novel pandemic disease pandemic influenza prevent public health relevance response screening tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Severe viral diseases are caused by a combination of virus-mediated cytopathic effects and either an acutely overactive or chronic inflammatory response. Diseases, such as keratoconjunctivitis by HSV1 or Adenovirus, encephalitis by HSV2 (in neonates) or West Nile virus, and emerging pandemic diseases, such as SARS and influenza, frequently cause severe complications and disabilities. These include blindness, severe mental retardation, pneumonia, acute respiratory distress and even death. Current therapies, when available, rely almost entirely on virus-specific antiviral drugs. However, elimination of the virus by antivirals does not prevent the inflammatory complications that result ultimately in disease manifestations. Therefore, corticosteroids are often used when inflammatory complications ensue. Corticosteroids, however, frequently lead to increased viral replication or reactivation of latent virus, thereby resulting in a difficult to interrupt vicious ycle. No single drug currently exists that can both inhibit viral replication and control deleterious inflammation. Our data, however, support a paradigm shifting hypothesis where simple and achievable metabolic changes in the tissue microenvironments can concurrently inhibit viral replication, modulate the inflammatory and angiogenic responses, and promote tissue healing, while allowing the development of a protective immune response. The depletion of the amino acids arginine or tryptophan by the enzymes arginase 1 (Ase-1) and indoleamine 2,3- dioxygenase (IDO) is one of the mechanisms by which the immune system regulates the magnitude of its response and prevents collateral damage to normal tissues during inflammation. It is also a mechanism frequently hijacked by tumors to escape an anti-tumor immune response. Here, we show that the in vivo depletion of a single amino acid has a potent and unexpected therapeutic effect in treating severe viral diseases. Arginine depletion inhibited a broad range of viral replication and promoted healing of tissues, while concurrently modulating deleterious inflammation and disease-associated neovascularization. This paradigm shifting observation leads us to propose that understanding the immunological and molecular pathways by which this therapeutic process occurs will not only create a new understanding of the metabolic mechanisms operating during severe viral and inflammatory diseases, but also create a platform for the development of novel therapies utilizing these natural immunoregulatory pathways.

描述（由申请人提供）：严重的病毒疾病是由病毒介导的细胞病变作用和急性过度活跃或慢性炎症反应的组合引起的。 HSV1或腺病毒的角膜结膜炎，例如HSV2（在新生儿）或西尼罗河病毒中，以及新兴的大流行疾病，例如SARS和流行性疾病，通常会引起严重的并发症和残疾。这些包括失明，严重的智力低下，肺炎，急性呼吸窘迫甚至死亡。当前的疗法（如果有）几乎完全依赖于病毒特异性抗病毒药。但是，抗病毒药消除病毒并不能阻止最终导致疾病表现的炎症并发症。因此，当炎症并发症发生时，经常使用皮质类固醇。然而，皮质类固醇经常导致潜伏病毒的病毒复制或重新激活增加，从而导致难以中断恶性。目前，没有一种可以抑制病毒复制和控制有害炎症的单一药物。然而，我们的数据支持范式转移假设，在该假说中，组织微环境的简单和可实现的代谢变化可以同时抑制病毒复制，调节炎症和血管生成反应，并促进组织愈合，同时允许保护性免疫反应的发展。氨基酸精氨酸或色氨酸的耗竭，酶精氨酸酶1（ASE-1）和吲哚美胺2,3-二氧酶（IDO）是免疫系统调节其反应的幅度并防止炎症过程中正常组织造成正常组织的幅度的机制之一。这也是一种经常被肿瘤劫持的机制，可以逃避抗肿瘤免疫反应。在这里，我们表明单个氨基酸的体内耗竭在治疗严重病毒疾病方面具有有效且意外的治疗作用。精氨酸的耗竭抑制了广泛的病毒复制并促进了组织的愈合，同时调节有害炎症和疾病相关的新血管形成。这种范式转移的观察结果使我们提出，这种治疗过程发生的免疫学和分子途径不仅会在严重的病毒和炎症性疾病期间对作业的代谢机制有了新的了解，还为利用这些自然免疫测定途径开发的新疗法创造了一个平台。