Host responses to Mycobacterium infection in Zebrafish.

描述(申请人提供)：结核病(TB)，在人类中是由结核分枝杆菌引起的，是全球传染病死亡的主要原因之一。现在的结核病病例比历史上任何时候都多，这在很大程度上要归因于艾滋病毒的流行。阻碍结核病流行的因素包括缺乏有效的疫苗，以及需要长期的多种药物治疗方案才能获得治愈。后者导致了广泛耐药菌株的选择和传播，使结核病成为前抗生素时代的致命疾病。结核是分枝杆菌与其脊椎动物宿主之间复杂的相互作用的结果。当被致病分枝杆菌感染时，巨噬细胞被招募到感染部位，在那里它们吞噬细菌。然而，巨噬细胞不是根除细菌，而是迁移到更深的组织中，以传播感染。然后招募更多未感染的巨噬细胞，并聚集成结核的标志性病理结构，即肉芽肿。长期以来，我们一直被认为是一种有利于宿主的结构，可以隔开感染，但我们发现，肉芽肿，至少在早期阶段，是细菌扩张和传播的载体。为了了解肉芽肿的发展过程，我们研究了海洋分枝杆菌，它是结核分枝杆菌的近亲，在它的自然宿主斑马鱼。斑马鱼是一种遗传上可追踪的脊椎动物，具有与哺乳动物相似的复杂免疫系统，在发育的前几周是透明的。这些功能允许对经过基因操纵的动物的感染进行详细的、连续的、实时的监测。这项建议的长期目标是更好地了解在肉芽肿发展过程中发生的宿主-病原体相互作用，目标是确定潜在的宿主导向疗法的靶点。在这 具体地说，我们将使用各种分子和遗传技术来探索肉芽肿发展过程中细胞死亡和招募的途径，并确定能够拦截这一过程的药物，以造福于宿主。

DESCRIPTION (provided by applicant): Tuberculosis (TB), which in humans is caused by Mycobacterium tuberculosis, is one of the leading causes of death from infectious diseases worldwide. There are more TB cases now than at any other time in history and this is largely attributed to the HIV epidemic. Factors that make it difficult to thwart the TB epidemic include the lack of an effective vaccine and the requirement for long multidrug treatment regimens to obtain cures. The latter has led to the selection and spread of extensively drug resistance strains that make TB the lethal disease it was in the pre-antibiotic era. TB results from complex interactions between mycobacteria and their vertebrate hosts. Upon infection by pathogenic mycobacteria, macrophages are recruited to the infection site where they phagocytose the bacteria. However, instead of eradicating the bacteria, macrophages migrate into deeper tissues serving to disseminate the infection. Additional uninfected macrophages are then recruited, and aggregate into the hallmark pathological structure of TB, the granuloma. Long thought to be a host beneficial structure that walls off the infection, we have found that the granuloma, at least in its early stages, serves as a vehicle for bacterial expansion and dissemination. To understand the process of granuloma development, we study Mycobacterium marinum, a close genetic relative of M. tuberculosis, in its natural host, the zebrafish. Zebrafish are genetically tractabl vertebrates with a similar complex immune system to that of mammals and are transparent in the early weeks of development. These features allow a detailed, serial, live-monitoring of infection in animals that have been genetically manipulated. The long term objective of this proposal is to better understand the host-pathogen interactions that occur during granuloma development, with the goal of identifying targets for potential host-directed therapeutics. In this proposal specifically, we will use a variety of molecular and genetic techniques to probe pathways of cell death and recruitment during granuloma development, and to identify pharmacological agents that intercept this process to the benefit of the host.