Genetic modulation of the host response to pulmonary TB

结核病（TB）是一个巨大的全球性健康问题。世界卫生组织估计，由结核分枝杆菌感染引起的结核病感染了20亿人，每年导致200万人死亡和800万新发病例。大多数结核病在感染时并不明显，而是在没有完全根除原发感染的人中潜伏疾病的重新激活。在潜伏感染中，有效的慢性宿主反应包含激活的巨噬细胞内的休眠结核微生物。细胞被募集以隔离感染的巨噬细胞，并且特异性T细胞持续诱导具有最小组织损伤的活化状态（免疫病理学）。虽然目前可用的抗生素可以杀死结核病微生物，但治疗时间长，价格昂贵，难以在资源贫乏的地区实施，并且对多重耐药微生物无效。迫切需要新的疗法来治疗活动性疾病并防止潜伏感染者的再激活。该提案将使用一种新的方法来解决这个问题，即基因操作以增强宿主对TB的免疫力并限制并发的免疫病理学。我们将构建载体以增加关键免疫分子的表达，T淋巴细胞活化细胞因子IL-12和IL-2,3，以及巨噬细胞效应分子LRG-47和吲哚胺2，3-双加氧酶（IDO）。已知这些分子参与了结核病的杀灭。我们将确定增加它们的表达是否会增加结核感染的巨噬细胞的杀伤能力，我们将研究这些分子如何相互作用以帮助清除结核杆菌。这一具有国际竞争力的赠款将进一步加深我们对结核病微生物复杂免疫反应的详细了解，并导致开发新的治疗结核病感染和预防潜伏疾病复发的疗法。

Tuberculosis (TB) is an enormous global health problem. The World Health Organisation estimates that TB, which is caused by infection with the bacteria Mycobacterium tuberculosis, infects 2 billion individuals, leading to 2 million deaths and 8 million new cases of disease per year. Most TB disease is not manifest at the time of infection, but is a reactivation of latent disease in people who do not completely eradicate the primary infection. In a latent infection an effective chronic host response contains dormant TB organisms inside activated macrophages. Cells are recruited to wall off infected macrophages and specific T cells continually induce the activate state with minimal tissue damage (immunopathology). Although currently available antibiotics can kill TB organisms, the treatment is prolonged, expensive, difficult to administer in poorly resourced regions and not effective against multi-drug resistant organisms. New therapies to treat both active disease and prevent reactivation in individuals who are latently infected are urgently required. This proposal will address this problem using a novel approach, namely gene manipulation to augment host immunity to TB and limit concurrent immunopathology. We will construct vectors to increase expression of the key immune molecules, the T lymphocyte activating cytokines IL-12 and IL-23, and the macrophage effector molecules LRG-47 and Indoleamine 2,3-Dioxygenase (IDO). These molecules are known to be involved in TB killing. We will determine if increasing their expression increases the killing capacity of TB-infected macrophages and we will examine how these molecules interact to aid clearance of the TB bacilli. This internationally competitive grant will further our detailed understanding of the complex immune response to TB organisms and lead to the development of novel therapies to treat TB infection and prevent reactivation of latent disease.