Inflammation and the Treatment of Primary Pneumonic Plague

项目摘要 鼠疫是由鼠疫耶尔森氏菌引起的最致命的一种疾病。疾病表现为快速的 一种进行性和高致死性的坏死性肺炎，通常在七天内死亡。如果抗生素治疗 如果没有在症状出现后24小时内使用，肺鼠疫是100%致命的。即使在 如果没有适当的抗生素治疗，最近的疫情证明死亡率仍然可以接近50%。的 肺鼠疫的快速发展及其难以治疗突出了对改进治疗方案的需求 以及对推动疾病进展的宿主因素有更全面的了解。这里提出的工作 旨在评估与抗生素治疗相结合的破坏性宿主免疫反应的抑制， 晚期肺鼠疫此外，监测肺中的宿主反应和生理参数 在疾病和治疗过程中，了解与生存相关的条件， 伴随着致命性。该提案的最终目标是确定治疗晚期 肺鼠疫有利于生存这项工作可能对肺鼠疫的治疗产生持久的影响， 以及由多种病原体引起的严重肺炎。该提案的具体目标如下： 目标1.抗生素和皮质类固醇联合治疗晚期肺鼠疫。初步 数据表明，用皮质类固醇丙酸氟替卡松预处理小鼠显著增加了存活率， 抗生素治疗肺鼠疫后死亡目标1旨在测试不同类别的 抗生素和皮质类固醇治疗晚期肺鼠疫，这是很难治疗，是非常致命的。 这是同类研究中第一个关注症状出现后的疾病治疗。目标1的目标是 为严重和致命的肺鼠疫制定最佳治疗方案。 目标二。评价肺炎治疗期间的肺功能和天然免疫应答 瘟疫限制肺部炎症增加小鼠存活率的发现提供了机会， 评估宿主在与生存性和致死性相关的条件下的反应。目标2旨在 评估宿主的炎症反应，免疫细胞库，以及肺中的生理条件， 肺鼠疫的疾病和治疗，以确定那些导致死亡的条件。此外，识别 有利于生存的肺部状况可能有助于确定发展的关键指标和目标， 有效的治疗方法。

Project Summary Pneumonic plague is the deadliest form of disease caused by Yersinia pestis. Disease manifests as a rapidly progressing and highly lethal necrotic pneumonia that is typically fatal within seven days. If antibiotic treatment is not administered within 24 hours after the onset of symptoms, pneumonic plague is 100% fatal. Even in the event of appropriate antibiotic therapy, as evidenced in recent outbreaks mortality can still approach 50%. The rapid progression of pneumonic plague and its difficulty to treat highlight a need for improved therapeutic options and a more complete understanding of the host factors driving disease progression. The work proposed here seeks to evaluate the suppression of damaging host immune responses coupled with antibiotic therapy to treat late-stage pneumonic plague. Further, host responses and physiological parameters in the lung are monitored during disease and treatment to understand those conditions that correlate with survival, and those that accompany lethality. The ultimate goals of the proposal are to identify conditions for treatment of late-stage pneumonic plague that favor survivability. This work may have lasting impact on pneumonic plague treatment, as well as severe pneumonia caused by a number of pathogens. The specific aims of the proposal are as follows: Aim 1. Co-treatment with antibiotics and corticosteroids for late-stage pneumonic plague. Preliminary data indicates that pretreating mice with the corticosteroid fluticasone propionate dramatically increases survival after antibiotic treatment of pneumonic plague. Aim 1 seeks to test co-administration of different classes of antibiotics and corticosteroids to treat late-stage pneumonic plague, which is difficult to treat and is highly fatal. This is the first study of its kind that focuses on treatment of disease after symptoms arise. The goal of Aim 1 is to develop an optimal treatment regime for severe and lethal pneumonic plague. Aim 2. Evaluate pulmonary function and innate immune responses during treatment of pneumonic plague. The finding that limiting pulmonary inflammation increases survival in mice offers the opportunity to evaluate host responses under conditions associated with both survivability and lethality. Aim 2 seeks to evaluate host inflammatory responses, immune cell repertoire, and physiological conditions in the lung during disease and treatment of pneumonic plague to identify those conditions that lead to lethality. Further, identifying pulmonary conditions conducive to survival may help to define key metrics and goals for the development of effective therapeutics.