Epithelial mechanisms of inducible resistance to AML-associated pneumonia

项目摘要 肺炎是急性髓细胞白血病（AML）患者的主要死亡原因。尽管不断 暴露的巨大表面积的微妙组织的外部环境，肺的内在 在感染建立之前，防御系统清除了大多数吸入和吸入的病原体。这些相同的粘膜 防御可以使用一种新的吸入疗法进行治疗刺激，该疗法包括非直观的Toll， 类受体（TLR）激动剂组合。这种可诱导的耐药与肺内快速 杀死病原体并防止小鼠死于由常见AML引起的其他致命肺炎， 相关病原体，即使在严重的化疗诱导的免疫功能低下的情况下。的 肺上皮细胞是诱导反应的主要效应物的发现使得这种方法 特别是对用于贫血AML患者有吸引力。本申请提出解剖分子 这一显著现象背后的机制有助于该技术的临床转化， AML患者，并促进对新型宿主-病原体相互作用的理解。 目的1将确定肺上皮细胞群体所需的诱导耐药AML相关的 肺炎将通过比较原发性AML病原体的诱导性杀伤来确定贡献。 小鼠和人上皮细胞，并通过TLR信号传导中细胞选择性缺陷的小鼠的功能测试。 目的2将确定诱导耐药是否受到白血病细胞或标准治疗的损害 细胞毒性或低甲基化AML方案。这将基于对以下的影响在体内和体外进行评估： 存活、病原体杀灭、上皮细胞活力、细胞活化、抗菌效应物和循环白细胞 目的3将剖析诱导抗性的分子机制，以确定保护是否可以 尽管共同给予现代靶向分子AML治疗，但仍然存在，并促进发现 新的上皮刺激。小鼠遗传操作和体外模型将鉴定所需的信号传导， 效应分子，并预计提供洞察不明TLR的协同作用观察。 这些拟议的研究预计将确定关键细胞，信号通路和效应分子， 可诱导抗性，促进发现更有效抗性诱导剂，探索非预期TLR 相互作用，评估诱导耐药与AML及其治疗的相互作用，确定AML人群 最有可能从治疗中受益，并促进这项技术快速转化为临床， AML患者在最脆弱的时期可以免受致命性肺炎的影响。

PROJECT SUMMARY Pneumonia is the leading cause of death among patients with acute myeloid leukemia (AML). Despite constant exposure of an immense surface area of delicate tissue to the external environment, the lungs' intrinsic defenses clear most aspirated and inhaled pathogens before infections are established. These same mucosal defenses can be therapeutically stimulated using a novel inhalational therapy comprised of a non-intuitive Toll- like receptor (TLR) agonist combination. This inducible resistance is associated with rapid intrapulmonary pathogen killing and prevents death in mice from otherwise lethal pneumonias caused by common AML- associated pathogens, even in the setting of severe chemotherapy-induced immunocompromise. The discovery that lung epithelial cells are principle effectors of the inducible response makes this approach particularly appealing for use in neutropenic AML patients. This application proposes to dissect the molecular mechanisms underlying this remarkable phenomenon to aid clinical translation of this technology for use in AML patients and to advance understanding of novel host-pathogen interactions. Aim 1 will identify the lung epithelial cell populations required for inducible resistance against AML-associated pneumonia. Contributions will be established by comparing inducible killing of AML pathogens by primary mouse and human epithelial cells and by functional testing of mice cell-selectively deficient in TLR signaling. Aim 2 will determine whether inducible resistance is impaired by leukemia cells or by treatment with standard cytotoxic or hypomethylating AML regimens. This will be assessed in vivo and in vitro based on effects on survival, pathogen killing, epithelial vitality, cellular activation, antimicrobial effectors, and circulating leukocytes Aim 3 will dissect the molecular mechanisms of inducible resistance to determine whether protection can persist despite co-administration of modern targeted molecular AML treatments, and to facilitate discovery of novel epithelial stimuli. Mouse genetic manipulation and in vitro models will identify required signaling and effector molecules and are expected to provide insight into the unexplained TLR synergy observed. The proposed studies are expected to identify critical cells, signaling pathways, and effector molecules of inducible resistance, promote discovery of more efficacious inducers of resistance, explore unanticipated TLR interactions, assess interactions of inducible resistance with AML and its treatments, identify AML populations most likely to benefit from the treatment, and facilitate the rapid translation of this technology into the clinic, so that AML patients can be protected from lethal pneumonia during periods of peak vulnerability.