INFLUENZA VIRUS EFFECTS ON MACROPHAGE VESICLE TRAFFIC

流感病毒对巨噬细胞囊泡运输的影响

• 批准号: 2071857
• 负责人: ROBERT J LOWY
• 金额: $ 6.5万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2071857
• 关键词: Orthomyxoviridae; acidity /alkalinity; clone cells; cytoplasm; cytoskeleton; endocytosis; host organism interaction; immunosuppression; intracellular transport; lysosomes; macrophage; phagocytosis; vesicle /vacuole; video microscopy

New and improved anti-microbial therapies are needed due to increasing immunocompromise populations and increasing spread of drug-resistant strains of microorganisms. Phagocytes (PC), important in pathogen clearance, can be inhibited so effectively by pathogens that virulence increases as PCs become the infectious agent reservoir and/or as susceptibility to secondary infections rises. Phagocytosis and endocytosis are among the important cellular functions suppressed by many notorious human pathogens, including influenza virus (IV), M. leprae and M. tuberculosis. These intracellular vesicle-based transport processes are central to both normal PC function and to most therapies, including drug delivery, modulation of activation and antigen processing. Not enough is known about either the specific phagosomal-endosomal processes affected or the physiological and biochemical mechanisms pathogens utilize to rationally design interventions to restore PC function. The major goal of this proposal is to determine what physiological changes occur in which phagosome-endosome processes resulting in failure of these anti-microbial cellular activities during IV interaction with a well-characterized phagocytic cell the J774.1 murine macrophage. Information on macrophage- pathogen effects is lagging that for other PCs, but during immunosuppression they can become the predominate remaining PC. IV is an important disease and many of its effects on PCs are similar to those of bacteria, but it is simpler and therefore the prospect of identifying important PC inhibitor mechanism(s) and improving anti-viral therapies is increased. The specific aims are: 1) Identify the extent and type of changes in macrophage intracellular trafficking pathways after exposure to IV. 2) Determine what changes occur in the intracellular physical-chemical environment of macrophages and intracellular compartments during early influenza virus exposure. 3) Investigate the effects of agents which either mimic or antagonize the IV-caused alterations in macrophage endosome and phagosome function. Quantitative digital video microscopy will be used to examine effects of IV on the J774 intracellular vesicle- based transport functions including the uptake and movement between compartments of molecular markers for specific endocytic and phagocytic functions. fluorescent probes will also be used to monitor the physical- chemical state of phagosomes and endosomes. It is expected that both the methodologies and cell biological findings will be applicable to understanding PC inhibition by other virus types, bacteria and parasites.

由于增加而需要新的和改进的抗微生物疗法 免疫功能低下的人群和抗药性的扩散不断增加 微生物菌株。 吞噬细胞（PC），在病原体中很重要 毒力的病原体可以有效地抑制清除率 随着PC成为传染性剂储层和/或AS的增加而增加 对继发感染的敏感性增加。吞噬作用和内吞作用 是许多臭名昭著的重要细胞功能之一 人类病原体，包括流感病毒（IV），M。Leprae和M. 结核。这些基于细胞的囊泡的运输过程是 正常PC功能和大多数疗法的中心，包括药物 递送，激活和抗原加工的调节。还不够 知道受影响的特定吞噬体 - 内体过程 生理和生化机制病原体用于 理性设计干预措施以还原PC功能。主要目标 该建议是确定发生的生理变化 吞噬体 - 粘体过程导致这些抗微生物失败 静脉相互作用期间的细胞活性与良好的特征 吞噬细胞J774.1鼠巨噬细胞。有关巨噬细胞的信息 病原体影响落后于其他PC，但在 免疫抑制它们可以成为剩余的PC。 iv是一个 重要疾病及其对PC的许多影响与 细菌，但这更简单，因此可以识别 重要的PC抑制剂机制和改善抗病毒疗法的是 增加。具体目的是：1）确定 暴露于巨噬细胞内运输途径的变化 iv。 2）确定细胞内物理化学发生了什么变化 早期巨噬细胞和细胞内室的环境 流感病毒暴露。 3）研究代理的影响 模仿或对抗巨噬细胞中的IV引起的变化 内体和吞噬体功能。定量数字视频显微镜 将用于检查IV对J774细胞内囊泡的影响 基于运输功能，包括吸收和移动 特异性内吞和吞噬细胞的分子标记室 功能。荧光探针也将用于监测物理 吞噬体和内体的化学状态。 期望这两个 方法和细胞生物学发现将适用于 了解其他病毒类型，细菌和寄生虫的PC抑制作用。