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: 7964751
• 负责人: Catharine Bosio
• 金额: $ 68.81万
• 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/7964751
• 关键词: Aerosols; Autoimmune Diseases; Bacteria; Bacterial Antigens; Biological; Breathing; CD14 gene; Cells; Dendritic Cells; Development; Disease; Francisella; Francisella tularensis; Goals; Human; Immune response; Immune system; Immunity; Immunosuppression; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-12; Invaded; Investigation; Laboratories; Left; Malignant Neoplasms; Molecular; Mus; Pathway interactions; Play; Production; Refractory; Research; Role; Route; Secondary to; Stimulus; Symptoms; Therapeutic; Time; Tularemia; Tumor Necrosis Factor-alpha; USSR; United States; Virulent; cytokine; extracellular; human TNF protein; microbial; monocyte; mortality; new therapeutic target; novel therapeutics; novel vaccines; pathogen; prevent; receptor; response; restoration; therapeutic vaccine; transmission process; vector; weapons

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 recently shown 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. One explanation for the poor responsiveness of human DC following infection with F. tularensis is that these cells lack CD14. CD14 appears to be a critical player in the elicitation of inflammation following exposure of cells to F. tularensis. Cells that lack CD14 are still susceptible to infection, but fail to produce pro-inflammatory cytokines. Furthermore, these cells become refractory to further stimulation by other microbial components. The specific role and the mechanism in which F. tularensis and its components interacts with CD14 is currently under investigation in the laboratory. F. tularensis 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 are currently dissecting the specific pathways and molecular mechanisms by which virulent F. tularensis modulates host responses in 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：土拉热弗朗西斯菌是土拉菌病的病原体，可通过多种途径感染人类，包括媒介传播。然而，吸入细菌和由此产生的肺炎土拉菌病是最危险的疾病形式。这是由于潜伏期短（3-5天），非特异性症状，以及未经治疗的个体的高死亡率（大于80%）。此外，F.美国和前苏联都已将土拉热病毒武器化，使其成为一种可行的生物武器。尽管对F.尽管土拉热菌在世界各地流行，但人们对这种细菌与宿主的动态相互作用，特别是在气溶胶感染后的相互作用知之甚少。 我的实验室最近发现，与鼠细胞相似，人类树突状细胞对F。土拉热，但不能产生促炎细胞因子或经历成熟。 此外，毒力F.土拉菌主动干扰人DC对次级刺激作出反应的能力。 人DC感染F.土拉热症的另一个原因是这些细胞缺乏CD 14。 CD 14似乎是细胞暴露于F后引发炎症的关键因素。土拉热。缺乏CD 14的细胞仍然容易受到感染，但不能产生促炎细胞因子。此外，这些细胞变得对其他微生物组分的进一步刺激不敏感。探讨了F.土拉热菌及其组分与CD 14相互作用的研究目前正在实验室进行。 F.土拉菌通过多种途径负调节人树突状细胞。 例如，如果细胞外细菌的复制受到限制，则人树突细胞响应于其他微生物刺激而产生TNF-α的能力得以恢复。 然而，没有观察到IL-12产生的类似恢复。 我们目前正在研究致病性F.土拉菌调节人树突细胞中的宿主应答。 除了有助于开发新的疫苗和治疗剂之外，鉴定能够负调节特定宿主途径（同时保持其他途径完整）的细菌产物可以为针对癌症和自身免疫性疾病的治疗剂提供新的靶标。