Epithelial mechanisms of inducible resistance to AML-associated pneumonia

描述（由申请人提供）：肺炎是急性髓性白血病（AML）患者的主要死亡原因。尽管脆弱组织的巨大表面积不断暴露于外部环境，但肺部的内在防御在感染建立之前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由非直观的Toll样受体（TLR）激动剂组合组成的新型吸入疗法在治疗上刺激。这种可诱导的耐药性与快速肺内病原体杀灭相关，并防止小鼠死于由常见AML相关病原体引起的其他致死性肺炎，即使在严重化疗诱导的免疫功能低下的情况下也是如此。肺上皮细胞是诱导性应答的主要效应物的发现使得这种方法特别适合用于血小板减少性AML患者。本申请提出剖析这一显著现象背后的分子机制，以帮助临床翻译该技术用于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对AML相关性肺炎。将通过比较原代小鼠和人上皮细胞对AML病原体的诱导性杀伤以及通过对TLR信号传导细胞选择性缺陷的小鼠进行功能测试来确定贡献。目的2将确定诱导耐药是否受到白血病细胞或标准细胞毒性或低甲基化AML方案治疗的损害。这将在体内和体外评估的基础上对生存的影响，病原体杀死，上皮细胞的活力，细胞活化，抗菌效应，和循环白细胞目的3将剖析诱导耐药的分子机制，以确定是否保护可以持续，尽管共同管理的现代靶向分子AML治疗，并促进发现新的上皮刺激。小鼠遗传操作和体外模型将确定所需的信号传导和效应分子，并有望提供对观察到的无法解释的TLR协同作用的深入了解。预计拟议的研究将鉴定诱导耐药的关键细胞、信号通路和效应分子，促进发现更有效的耐药诱导剂，探索非预期的TLR相互作用，评估诱导耐药与AML及其治疗的相互作用，鉴定最有可能从治疗中受益的AML人群，并促进该技术快速转化为临床，这样AML患者就可以在最脆弱的时期免受致命性肺炎的伤害。

DESCRIPTION (provided by applicant): 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 whethe 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.