Modulation of Human Cells by Virulent Francisella tularensis

有毒土拉弗朗西斯菌对人体细胞的调节

• 批准号: 8157079
• 负责人: Catharine Bosio
• 金额: $ 68.43万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157079
• 关键词: Cells; Francisella tularensis; Human; Virulent; Cells; Francisella tularensis; Human; Virulent

Summary: Francisella tularensis, the causative agent for tularemia, can infect humans by a number of routes, including vector-borne transmission. However, it is inhalation of the bacterium, and the resulting pneumonic tularemia, that represents the most dangerous form of disease. This is due to the short incubation time (3-5 days), non-specific symptoms, and a high mortality rate (greater than 80%) in untreated individuals. Furthermore, F. tularensis has been weaponized by both the United States and the former Soviet Union making it a viable candidate for use as a biological weapon. Despite over 80 years of research on F. tularensis around the world, very little is understood about the dynamic interaction of this bacterium with the host, especially following aerosol infection. My laboratory has established that, similarly to murine cells, human dendritic cells are acutely susceptible to infection with F. tularensis, but fail to produce pro-inflammatory cytokines or undergo maturation. Further, virulent F. tularensis actively interferes with the ability of human DC to respond to secondary stimuli. Understanding the mechanism by which F. tularensis actively suppresses DC function is a central directive of my laboratory. We are tackling this directive in two different ways. First, we are analyzing the role Francisella lipids play in mediating anti-inflammatory responses. Structures present on the surface of bacteria are the first components encountered by the host cell. Thus, it is possible that, in the context of F. tularensis infections, these structures contribute to the early, rapid suppression of human dendritic cells. Bacterial lipids represent one such structure. Preliminary evidence in our lab suggests that lipids associated with the outer membrane of F. tularensis can potently suppress inflammatory responses in human dendritic cells. We are currently identifying the specific lipid(s) responsible for this suppression and the mechanism by which they interfere with human dendritic cell functions. Second, we are exploring the intracellular host pathways modulated by F. tularensis, which negatively regulates human dendritic cells through multiple pathways. For example, if the replication of extracellular bacteria is restricted, the ability of human dendritic cells to produce TNF-alpha in response to other microbial stimuli is restored. However, a similar restoration of IL-12 production is not observed. We have demonstrated that rapid induction of IFN-beta by F. tularensis potently suppresses production of IL-12 in human dendritic cells. We are currently dissecting the specific pathways and molecular mechanisms by which IFN-beta modulates host responses in F. tularensis infected human dendritic cells. In addition to aiding in the development of novel vaccines and therapeutics, identification of bacterial products capable of negatively regulating specific host pathways (while leaving others intact) may provide new targets for therapeutics directed against cancer and autoimmune diseases.

摘要：francisella tularensis是t骨的病因，可以通过许多路线感染人类，包括媒介传播。然而，这是最危险的疾病形式的细菌和由此产生的肺炎。这是由于未经治疗的个体的短期孵育时间（3-5天），非特异性症状和高死亡率（大于80％）。此外，F。tularensis已被美国和前苏联武器化，使其成为可行的生物武器候选人。尽管在全球范围内进行了80多年的研究，但对这种细菌与宿主的动态相互作用的了解很少，尤其是在气溶胶感染之后。 我的实验室已经确定，与鼠细胞类似，人树突状细胞非常容易感染f。tularensis，但无法产生促炎性细胞因子或经历成熟。 此外，有毒的F. tularensis会积极干扰人类直流对继发刺激的能力。了解F. tularensis积极抑制直流功能的机制是我实验室的中心指令。 我们以两种不同的方式解决该指令。 首先，我们正在分析弗朗西斯拉脂质在介导抗炎反应中的作用。 细菌表面上存在的结构是宿主细胞遇到的第一个组件。 因此，在F. tularensis感染的背景下，这些结构有助于早期，快速抑制人的树突状细胞。 细菌脂质代表这样一种结构。我们实验室中的初步证据表明，与F. tularensis的外膜相关的脂质可以在人树突状细胞中有效抑制炎症反应。我们目前正在识别负责这种抑制作用的特定脂质以及它们干扰人类树突状细胞功能的机制。 其次，我们正在探索由F. tolarensis调节的细胞内宿主途径，该途径通过多种途径对人类树突状细胞负调节。 例如，如果限制了细胞外细菌的复制，则恢复了人树突状细胞产生TNF-α以响应其他微生物刺激的能力。 但是，未观察到类似的IL-12产生的恢复。 我们已经证明，tularensis对IFN-β的迅速诱导会在人树突状细胞中有效抑制IL-12的产生。我们目前正在解剖特定的途径和分子机制，IFN-beta调节了f。tularensis感染的人树突状细胞中的宿主反应。 除了帮助开发新型疫苗和治疗剂外，还可以鉴定能够负调节特定宿主途径的细菌产品（同时使其他宿主途径完好无损）可以为针对癌症和自身免疫性疾病的疗法提供新的靶标。