Immunity to Pneumonic Tularemia

对肺炎兔热病的免疫力

• 批准号: 8336235
• 负责人: Catharine Bosio
• 金额: $ 106.28万
• 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/8336235
• 关键词: Address; Aerosols; Animals; Anti-Inflammatory Agents; Antibiotics; Attenuated; Bacteria; Biological; Breathing; Cells; Collaborations; Data; Dendritic Cells; Detection; Development; Disease; Euthanasia; Extrinsic asthma; Family member; Francisella; Francisella tularensis; Goals; Hospitals; Host Defense; Human; Immune system; Immunity; Immunology; Immunosuppression; In Vitro; Individual; Infection; Inflammation; Inflammatory Response; Integration Host Factors; Interferon Type II; Interferon-beta; Interferons; Interleukin-12; Journals; Laboratories; Lipids; Lung; Modeling; Molecular; Mus; Phase; Pneumonia; Production; Proteins; Publishing; Research; Resolution; Role; Route; Saint Jude Children' s Research Hospital; Source; Stimulus; Symptoms; System; Testing; Time; Tularemia; USSR; United States; Universities; Virulent; Work; antimicrobial; cytokine; in vivo; interleukin-12 subunit p35; interleukin-12 subunit p40; mortality; mouse model; novel therapeutics; novel vaccines; prevent; response; transmission process; vector; volunteer; 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%). 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. In the last several years my laboratory has provided abundant evidence that one of the primary mechanisms by which F. tularensis successfully infects and replicates in the host is via active interference with development of inflammatory responses in the lungs. A major hurdle in studying virulent F. tularensis in vivo is that animals require euthanasia within a few days of infection. This does not allow reliable assessment of the interaction of the bacterium with the host immune system. To overcome this obstacle we developed a model using antibiotics in which we provoke slow clearance of F. tularensis and survival among infected animals. This model has both identified host requirements for survival of tularemia and, importantly, demonstrated that many of these requirements are different than those observed using attenuated strains. Specifically, we have shown that both IL-12p40 and IL-12p35 are essential in defense against F. tularensis infection. We are now utilizing this model to identify host factors that contribute to the exacerbation of F. tularensis infection. We have also identified components of the bacterium that contribute to dampening inflammatory responses in the host using in vitro systems. In collaboration with our colleagues, Richard Lee (St. Jude Childrens Hospital) and Pam Small (Special Volunteer, Rocky Mountain Labs) we have shown that lipids isolated from virulent F. tularensis, but not attenuated strains, fail to stimulate inflammatory responses and (importantly) interfere with the ability of host cells to respond to unrelated stimuli. We are currently testing the capability of these lipids to interfere with inflammatory responses in vivo. Data gathered from these studies will expand our understanding of tularemia and enable development of novel therapeutics and vaccines. Additionally, these lipids may be adapted for use as potent anti-inflammatory agents for use against unrelated conditions such as allergic asthma. Finally, we observed that virulent F. tularensis stimulates rapid production of IFN-beta as a mechanism to selectively inhibit production of IL-12 in human dendritic cells. The findings were recently published in the Journal of Immunology. Further, unlike infection with attenuated strains IFN-b did not aid in resolution of infection nor did the presence of this host cytokine contribute to activation of the inflammasome. We are extended these observations to our mouse model and have shown that F. tularensis evades activation of the inflammasome. We are currently identifying how the bacterium evades this detection and the specific inflammasome components it modulates to accomplish this evasion.

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），非特异性症状和高死亡率（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。 在过去的几年里，我的实验室提供了大量的证据，证明F。土拉菌在宿主中成功感染和复制是通过主动干扰肺部炎症反应的发展。研究F.土拉热病在体内是动物需要在感染的几天内安乐死。 这不允许对细菌与宿主免疫系统的相互作用进行可靠的评估。 为了克服这一障碍，我们开发了一种使用抗生素的模型，在该模型中，我们引起F的缓慢清除。土拉热病和受感染动物的存活率。 该模型既确定了土拉菌存活的宿主要求，而且重要的是，证明了这些要求中的许多与使用减毒株观察到的要求不同。 具体地说，我们已经证明IL-12 p40和IL-12 p35在防御F.土拉菌感染 我们现在正在利用这个模型来确定宿主因素，有助于F。土拉菌感染 我们还确定了细菌的成分，有助于抑制炎症反应的主机使用体外系统。 在与我们的同事Richard Lee（圣裘德儿童医院）和Pam Small（落基山实验室特别志愿者）的合作中，我们已经证明了从有毒的F。土拉热菌而不是减毒株不能刺激炎症反应，并且（重要的是）干扰宿主细胞对无关刺激作出反应的能力。 我们目前正在测试这些脂质在体内干扰炎症反应的能力。 从这些研究中收集的数据将扩大我们对兔热病的理解，并使新的治疗方法和疫苗的开发成为可能。 此外，这些脂质可适于用作有效的抗炎剂，用于对抗不相关的病症，如过敏性哮喘。 最后，我们观察到，强毒F。土拉热刺激IFN-β的快速产生，作为选择性抑制人树突细胞中IL-12产生的机制。 这项研究结果最近发表在《免疫学杂志》上。 此外，与用减毒株感染不同，IFN-b不帮助感染的消退，这种宿主细胞因子的存在也不有助于炎性体的活化。 我们将这些观察结果扩展到我们的小鼠模型，并表明F。土拉热避免了炎性小体的激活。 我们目前正在确定细菌如何逃避这种检测以及它调节以实现这种逃避的特定炎性体组分。