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。 我们的实验室专注于细菌的组分，这些组分是宿主在感染后首先遇到的，与细菌外膜相关的脂质和碳水化合物。 已知细菌脂质和碳水化合物是其他病原体的重要毒力因子。 然而，关于脂质和碳水化合物在促进F.土拉热。 在过去一年中，我们取得了三项重要进展。 我们已经证明，从F。土拉菌在体外和体内广泛抑制炎症反应，鉴定了介导这种抑制所需的两种宿主受体，并鉴定了暴露于脂质的细胞中失活的特定信号转导分子。 我们还确定了一个主要的机制，完整的，可行的F。土拉菌病通过编码促炎细胞因子的mRNA的去稳定化而快速干扰炎症反应的诱导，所有这些都是土拉菌病存活所必需的。 我们正在继续确定宿主和细菌成分在这种不稳定中发挥的具体作用。 最后，我们做出了令人惊讶的发现，即特定的B细胞亚群有助于肺炎土拉菌病的恶化，而不是作为保护性细胞亚群，并且发现当暴露于弗朗西斯菌时，这些细胞产生的IL-10有助于在肺中观察到的免疫抑制。 最近的工作集中在鉴定弗朗西斯菌外表面存在的有助于抑制宿主炎症反应的碳水化合物。 我们与爱荷华州大学的布拉德利琼斯博士合作，测试各种F。土拉热菌具有在碳水化合物合成中的特异性突变，因为它们能够逃避和抑制促炎反应。