Metabolic approaches to treat severe viral and inflammatory diseases

描述(申请人提供)：严重的病毒性疾病是由病毒介导的细胞病变效应和剧烈过度活动或慢性炎症反应的组合引起的。单纯疱疹病毒1型或腺病毒引起的角结膜炎、单纯疱疹病毒2型脑炎(新生儿)或西尼罗河病毒等疾病，以及SARS和流感等新出现的大流行疾病，往往会导致严重的并发症和残疾。这些疾病包括失明、严重智力低下、肺炎、急性呼吸窘迫甚至死亡。目前的治疗方法，如果可行，几乎完全依赖于针对病毒的抗病毒药物。然而，通过抗病毒药物消除病毒并不能防止最终导致疾病表现的炎性并发症。因此，当炎症并发症接踵而至时，经常使用皮质类固醇。然而，皮质类固醇经常导致病毒复制增加或潜伏病毒重新激活，从而导致难以中断的恶性循环。目前还没有一种药物可以同时抑制病毒复制和控制有害的炎症。然而，我们的数据支持一种范式转换假说，即组织微环境中简单且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，促进组织愈合，同时允许发展保护性免疫反应。精氨酸或色氨酸被精氨酸酶1(ASE-1)和吲哚胺2，3-双加氧酶(IDO)耗尽是免疫系统调节其反应幅度和防止炎症过程中对正常组织的附带损害的机制之一。它也是一种经常被肿瘤劫持以逃避抗肿瘤免疫反应的机制。在这里，我们展示了体内单一氨基酸的耗尽在治疗严重的病毒性疾病方面具有强大的和意想不到的治疗效果。精氨酸耗竭抑制了广泛的病毒复制，促进了组织的愈合，同时调节了有害的炎症和与疾病相关的新生血管。这种范式转换的观察导致我们提出，了解这一治疗过程发生的免疫学和分子途径不仅将对严重病毒和炎症性疾病期间的代谢机制产生新的理解，而且还将为利用这些自然免疫调节途径开发新的治疗方法创造一个平台。

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.