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）患者死亡的主要原因。尽管脆弱组织的巨大表面积不断暴露在外部环境中，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一种由非直观的Toll样受体（TLR）激动剂组合组成的新型吸入疗法进行治疗性刺激。这种诱导耐药与肺内病原体的快速杀伤有关，并防止小鼠死于由常见AML相关病原体引起的致命性肺炎，即使在化疗诱导的严重免疫功能低下的情况下也是如此。发现肺上皮细胞是诱导性反应的主要效应器，使得这种方法对中性粒细胞减少的AML患者特别有吸引力。本应用建议剖析这一显著现象背后的分子机制，以帮助该技术用于AML患者的临床翻译，并促进对新型宿主-病原体相互作用的理解。目的1将确定抗aml相关肺炎诱导抗性所需的肺上皮细胞群。通过比较原代小鼠和人上皮细胞对AML病原体的诱导杀伤，以及对TLR信号选择性缺陷的小鼠细胞的功能测试，将得出结论。目的2将确定诱导性耐药是否受到白血病细胞或标准细胞毒性或低甲基化AML治疗方案的损害。这将在体内和体外根据对存活、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的影响进行评估。Aim 3将分析诱导耐药的分子机制，以确定在联合使用现代靶向分子AML治疗的情况下，保护是否能够持续，并促进发现新的上皮刺激。小鼠遗传操作和体外模型将识别所需的信号和效应分子，并有望为观察到的未解释的TLR协同作用提供见解。拟议的研究预计将确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，探索意想不到的TLR相互作用，评估诱导耐药与AML及其治疗的相互作用，确定最有可能从治疗中受益的AML群体，并促进该技术快速转化为临床。从而使急性髓性白血病患者在最易感染的时期免受致命性肺炎的侵害。

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.