Inducible epithelial resistance: a program investigating mechanisms to protect against acute and chronic complications of pneumonia

项目摘要-摘要 肺炎每年导致数百万人死亡，并在许多幸存者中造成慢性健康并发症。然而， 尽管不断地将巨大的表面积暴露在外部环境中，但肺的内在 防御系统在感染确定之前清除了大多数病原体。这些粘膜防御系统可以 使用一种新的吸入疗法进行治疗刺激，该吸入疗法由非直觉的、协同的合成 模式识别受体激动剂组合。这种可诱导的耐药性导致快速的肺内 杀死病原体并防止由细菌、病毒或其他致命性肺炎引起的小鼠死亡 真菌病原体。肺上皮细胞是这种反应的主要媒介，而对呼吸道和 肺泡细胞对于白细胞依赖免疫功能受损的患者来说是偶然的。海流 一项提案支持一项研究这种现象预防急性呼吸道感染的机制的计划 肺炎和慢性肺病，使人们更好地了解天然的粘膜防御，识别 最有可能受益的人群，并促进制定更有效的干预措施 肺炎。该计划旨在产生最大的科学进步和最有力的培训 环境，因此，调查不是针对预先指定的里程碑，而是在四个自我维持的范围内进行 连续寻求可测试假设的企业然后迭代地构建所生成的数据。 企业1剖析了驱动肺炎保护的协同信号机制，以揭示如何 优化的重合检测可以通过新的传感器和放大器最大化保护信号。 企业2追求可诱导的活性氧产生的机制来解释感知 信号事件促进了多源抗菌剂挥发性物种的协调产生。 企业3解决了实现广泛病原体杀灭的效应器机制，以更好地定义范围 保护和研究抗菌肽和活性氧物种之间的未知相互作用。 企业4号探索了促进持久诱导的免疫调节效应的机制，以确定 可诱导的抵抗力如何在延长的时间尺度上对哮喘和免疫病理学发挥作用。 这些努力将确定关键的信号事件和诱导抗性的效应机制，揭示 意想不到的传感器相互作用，有助于发现更有效的抗性诱导剂，并加快 将这项技术转化为临床，在患者易受攻击的高峰期保护患者。

PROJECT SUMMARY-ABSTRACT Pneumonias cause millions of deaths annually and cause chronic health complications in many survivors. Yet, despite constant exposure of an immense surface area to the external environment, the lungs’ intrinsic defenses clear most pathogens before infections are established. These mucosal defenses can be therapeutically stimulated using a novel inhaled therapy comprised of a non-intuitive, synergistic synthetic pattern recognition receptor agonist combination. This inducible resistance results in rapid intrapulmonary pathogen killing and prevents death in mice from otherwise lethal pneumonias caused by bacterial, viral or fungal pathogens. Lung epithelial cells are principal mediators of this response, and reliance on airway and alveolar cells is fortuitous for patients with leukocyte-dependent immunocompromising conditions. The current proposal supports a program investigating the mechanisms by which this phenomenon protects against acute pneumonia and chronic lung disease, allowing greater understanding of native mucosal defenses, identifying populations most likely to benefit, and promoting development of more efficacious interventions against pneumonia. This program is designed to produce the greatest scientific advance and most robust training environment, so rather than targeting pre-specified milestones, investigations align within four self-sustaining enterprises that serially pursue testable hypotheses then iteratively build upon the generated data. Enterprise 1 dissects the mechanisms of synergistic signaling that drive pneumonia protection to reveal how optimized coincident detection can maximize the protective signal through novel sensors and amplifiers. Enterprise 2 pursues the mechanisms of inducible reactive oxygen species production to explain how sensing and signaling events promote coordinated generation of multisource antimicrobial volatile species. Enterprise 3 addresses the effector mechanisms that achieve broad pathogen killing to better define the extent of protection and investigate unexplored interactions of antimicrobial peptides and reactive oxygen species. Enterprise 4 explores the mechanisms that promote durably induced immunomodulatory effects to determine how inducible resistance exerts effects against asthma and immunopathology over extended time scales. These efforts will identify critical signaling events and effector mechanisms of inducible resistance, reveal unanticipated sensor interactions, facilitate discovery of more efficacious inducers of resistance, and expedite the translation of this technology into the clinic to protect patients during periods of peak vulnerability.