Immunity to Pneumonic Tularemia

对肺炎兔热病的免疫力

• 批准号: 8946416
• 负责人: Catharine Bosio
• 金额: $ 75.4万
• 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/8946416
• 关键词: Aerosols; B-Lymphocyte Subsets; Bacteria; Biological; Breathing; Carbohydrates; Cells; Collaborations; Development; Disease; Francisella; Francisella tularensis; Goals; Human; Immune response; Immunity; Immunosuppression; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Iowa; Laboratories; Lipids; Lung; Mediating; Membrane; Messenger RNA; Mutation; Organism; Pathogenesis; Phase; Play; Production; Receptor Signaling; Research; Role; Route; Signal Pathway; Signal Transduction; Surface; Symptoms; Testing; Time; Tularemia; USSR; United States; Universities; Virulence Factors; Work; cytokine; in vivo; mortality; mouse model; novel therapeutics; novel vaccines; pathogen; prevent; receptor; transmission process; vector; weapons

Francisella tularensis, the causative agent for tularemia, can infect humans by a number of routes, including vector-borne transmission. However, inhalation of the bacterium, and the resulting pneumonic tularemia, is 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. Our laboratory has focused on components of the bacterium that are the first encountered by the host following infection, lipids and carbohydrates associated with the outer membrane of the bacteria. Bacterial lipids and carbohydrates are known to be important virulence factors for other pathogens. However, little is known about the role the lipids and carbohydrates play in facilitating infection with F. tularensis. Over the past year we have made three important advances. We have shown that lipids isolated from F. tularensis broadly inhibit inflammatory responses in vitro and in vivo, identified two host receptors required to mediate this suppression and identified specific signal transduction molecules inactivated in cells exposed to lipid. We also identified that a major mechanism by which intact, viable F. tularensis rapidly interferes with induction of inflammatory responses is via destabilization of mRNA encoding pro-inflammatory cytokines all of which are required for survival of tularemia. We are continuing to identify the specific role host and bacterial components play in this destabilization. Finally, we made the surprising finding that a specific B cell subset contributes to the exacerbation of pneumonic tularemia rather than serving as a protective cell subset and found that production of IL-10 by these cells when exposed to Francisella contributes to the immunosuppression observed in the lung. More recent work is focused on identifying carbohydrates present in the outer surface of Francisella that contribute to suppression of host inflammatory responses. In collaboration with Dr. Bradley Jones at the University of Iowa we are testing various F. tularensis with specific mutations in carbohydrate synthesis for their ability to evade and inhibit pro-inflammatory responses.

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，吸入这种细菌并由此引发肺炎土拉菌病是最危险的疾病。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。