Host-Responses to Mycobacterium Infection in Zebrafish

斑马鱼宿主对分枝杆菌感染的反应

• 批准号: 8290839
• 负责人: LALITA RAMAKRISHNAN
• 金额: $ 38.6万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8290839
• 关键词: Animals; Antibiotic Resistance; Antibiotics; Apoptosis; Apoptotic; Bacteria; Biological Assay; CD36 gene; Caspase; Cause of Death; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Chemotaxis; Cleaved cell; Communicable Diseases; Complex; Coupled; Critical Pathways; Development; Disease; Drug Delivery Systems; Drug resistance; Epidemic; Epithelial Cells; Epithelium; Funding; Gelatinase B; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Screening; Genetic Techniques; Genetic Variation; Genotype; Genus Mycobacterium; Goals; Granuloma; Growth; HIV; Human; Image; Immune response; Immune system; Infection; Inflammation; Intercept; Intervention; Kinetics; Larva; Lead; Lesion; Life; Maintenance; Mammals; Maps; Mediating; Microscopy; Modeling; Molecular; Molecular Genetics; Monitor; Mutation; Mycobacterium Infections; Mycobacterium marinum; Mycobacterium tuberculosis; Necrosis; Optics; Outcome; Pathway interactions; Peptides; Phagocytosis; Predisposition; Process; Quantitative Microscopy; Recording of previous events; Recruitment Activity; Relative (related person); Research; Resistance; Resolution; Severities; Site; Staging; Structure; Techniques; Testing; Therapeutic; Time; Tissues; Treatment Protocols; Tuberculosis; Tumor Necrosis Factor-alpha; Vaccines; Vertebrates; Virulence; Virulence Factors; Virulent; Work; Zebrafish; base; cell type; chemokine; extracellular; genome sequencing; in vivo; leukotriene A4 hydrolase; macrophage; migration; mutant; mycobacterial; non-compliance; pathogen; programs; rapid technique; receptor; resistant strain; response; scavenger receptor; tool; tuberculosis granuloma

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. PUBLIC HEALTH RELEVANCE: Tuberculosis is a leading cause of death with more cases now than at any previous time. TB has been difficult to eradicate due to a requirement for long treatment regimens, which lead to non-compliance, and the development of antibiotic resistance. This proposal will identify strategies and molecules that are exploited by the bacteria to produce disease, so as to direct new classes of host-targeting drugs to treat TB. It will also identify host markers of susceptibility that will aid in the development of more efficacious, personalized treatment regimens.

描述（由申请人提供）： 结核病 (TB) 在人类中由结核分枝杆菌引起，是全世界传染病导致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，这在很大程度上归因于艾滋病毒的流行。难以阻止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，使结核病成为抗生素之前时代的致命疾病。结核病是分枝杆菌与其脊椎动物宿主之间复杂相互作用的结果。被病原分枝杆菌感染后，巨噬细胞被募集到感染部位，吞噬细菌。然而，巨噬细胞并没有消灭细菌，而是迁移到更深的组织中，从而传播感染。然后招募更多未感染的巨噬细胞，并聚集成结核病的标志性病理结构，即肉芽肿。长期以来，肉芽肿被认为是一种抵御感染的有益宿主结构，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，我们在其天然宿主斑马鱼中研究了海分枝杆菌（结核分枝杆菌的近亲）。斑马鱼是一种遗传易驯化的脊椎动物，具有与哺乳动物相似的复杂免疫系统，并且在发育的最初几周是透明的。这些功能可以对经过基因改造的动物的感染情况进行详细、连续、实时的监测。该提案的长期目标是更好地了解肉芽肿发展过程中发生的宿主与病原体的相互作用，目的是确定潜在的宿主导向治疗的靶标。在这个 具体来说，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补充的途径，并确定拦截这一过程以造福于宿主的药物制剂。 公共卫生相关性：结核病是导致死亡的主要原因，现在的病例数量比以往任何时候都要多。由于需要长期治疗方案，从而导致不依从性和抗生素耐药性的发展，结核病一直难以根除。该提案将确定细菌利用的策略和分子 产生疾病，从而指导新型宿主靶向药物治疗结核病。它还将识别宿主的易感性标记，这将有助于开发更有效、个性化的治疗方案。