Inflammation and the Treatment of Primary Pneumonic Plague

项目摘要 肺鼠疫是由鼠疫耶尔森氏菌引起的最致命的疾病形式。疾病表现为一种迅速的 进展性和高致命性坏死性肺炎，通常在七天内致命。如果抗生素治疗 如果在症状出现后24小时内不给药，肺鼠疫是100%致命的。即使是在 如最近暴发的疫情所证明的那样，如果进行适当的抗生素治疗，死亡率仍可接近50%。这个 肺鼠疫的迅速发展及其治疗的困难凸显了改进治疗方案的必要性 以及对推动疾病进展的宿主因素有更全面的了解。在这里提出的工作 寻求评估抑制破坏性宿主免疫反应与抗生素治疗相结合的治疗 晚期肺炎鼠疫。此外，还监测肺部的宿主反应和生理参数 在疾病和治疗期间，了解那些与生存相关的条件，以及那些 伴随着致命的。该提案的最终目标是确定晚期糖尿病的治疗条件。 有利于生存的肺炎瘟疫。这项工作可能会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。该建议的具体目标如下： 目的1.联合应用抗生素和糖皮质激素治疗晚期肺鼠疫。初步 数据表明，用丙酸皮质类固醇氟替卡松预处理小鼠可显著提高存活率。 在肺炎鼠疫抗生素治疗后。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炎鼠疫，这种鼠疫很难治疗，而且具有很高的致命性。 这是第一项以症状出现后疾病治疗为重点的此类研究。目标1的目标是 为重症和致命性肺鼠疫制定最佳治疗方案。 目的2.评价肺炎治疗中的肺功能和先天免疫反应 瘟疫。限制肺部炎症可以增加小鼠的存活率，这一发现为 评估宿主在与生存能力和致命性相关的条件下的反应。《目标2》寻求 评估宿主炎症反应、免疫细胞库和肺内的生理状况 肺鼠疫的疾病和治疗，以确定导致死亡的条件。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.