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: 8336307
• 负责人: Catharine Bosio
• 金额: $ 72.9万
• 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/8336307
• 关键词: Aerosols; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Autoimmune Diseases; Bacteria; Biological; Breathing; Cell physiology; Cells; Cessation of life; Data; Dendritic Cells; Development; Disease; Francisella; Francisella tularensis; Genes; Goals; Host Defense; Human; Immune response; Immune system; Immunosuppression; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferon-beta; Interleukin-12; Interleukin-18; Invaded; Jail; Laboratories; Left; Lipids; Malignant Neoplasms; Mediating; Membrane; Molecular; Mus; Natural Immunity; Pathway interactions; Play; Process; Production; Research; Role; Route; Secondary to; Stimulus; Structure; Surface; Symptoms; Time; Tularemia; Tumor Necrosis Factor-alpha; USSR; United States; Virulent; adaptive immunity; cytokine; extracellular; human TNF protein; microbial; mortality; new therapeutic target; novel therapeutics; novel vaccines; pathogen; prevent; response; restoration; 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 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. Finally, activation of the host cell inflammasome and subsequent secretion of the inflammatory cytokines IL-1beta and IL-18 is thought to be a central feature of host defense against a wide range of pathogens. Indeed, it has been shown that attenuated strains of F. tularensis are capable of activating the inflammasome resulting in cel death and release of IL-1b. However, our data suggests that virulent F. tularensis evades and interferes with this process. Currently, we are examining the role of the inflammasome, IL-1b and IL-18 in defense against tularemia. Additionally, our gaol is to determine how virulent F. tularensis disrupts this process.

摘要：土拉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，吸入这种细菌以及由此产生的肺炎土拉菌病是最危险的一种疾病。这是由于潜伏期短（3-5天）、非特异性症状和未经治疗个体的高死亡率（大于80%）。此外，美国和前苏联都将土拉菌武器化，使其成为一种可行的生物武器。尽管全球范围内对土拉菌进行了80多年的研究，但人们对这种细菌与宿主的动态相互作用知之甚少，尤其是在气溶胶感染之后。