Immunity to Pneumonic Tularemia

对肺炎兔热病的免疫力

基本信息

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
项目类别：
财政年份：
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

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

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项目摘要

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.

弗朗西斯菌（Francisella tularensis）是图菌病的病因，可以通过许多路线感染人类，包括媒介传播。然而，吸入细菌以及由此产生的肺炎症状是最危险的疾病形式。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。我们的实验室专注于细菌的成分，这是宿主感染后第一次遇到的，脂质和与细菌外膜相关的碳水化合物。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，对于脂质和碳水化合物在促进f菌感染中的作用知之甚少。在过去的一年中，我们取得了三个重要的进步。我们已经表明，从F. tularensis分离出的脂质在体外和体内广泛抑制了炎症反应，鉴定出了介导这种抑制的两个宿主受体，并确定了在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，完整，可行的F. tularensis迅速干扰炎症反应的一种主要机制是通过破坏编码促炎细胞因子的mRNA的稳定，而这些促炎细胞因子均需要用于生存的toluare症。我们将继续确定在这种不稳定中的特定角色宿主和细菌成分所起的作用。最后，我们提出了一个令人惊讶的发现，特定的B细胞子群有助于肺炎肿瘤的加剧，而不是作为保护性细胞子群，发现这些细胞在暴露于Francisella时产生的IL-10产生IL-10，从而有助于在肺中观察到的免疫抑制。最近的工作集中在识别弗朗西塞拉外表面中存在的碳水化合物，这有助于抑制宿主炎症反应。与爱荷华大学的布拉德利·琼斯（Bradley Jones）博士合作，我们正在测试具有碳水化合物合成中特定突变的各种tularensis，以逃避和抑制促炎反应的能力。