Reactive Oxygen Species in Anti-Viral Airway Host Defense

描述（申请人提供）：甲型流感是一种典型的新发疾病。基因重组和/或对新宿主的适应可能导致灾难性的大流行，死亡率很高。流感病毒在呼吸道上皮中感染和复制，并诱导由中性粒细胞和单核细胞组成的炎性浸润。原发性先天免疫应答起始于气道上皮的顶端表面，在最近鉴定的NADPH氧化酶Duox所在的位置。Duox产生活性氧物质，并与伤口愈合以及pH和氧化还原环境的变化有关。这些特征使Duox成为空气微生物致病过程中局部免疫反应的理想参与者。该项目使用正向遗传学来阐明Duox蛋白如何调节抗病毒宿主防御所必需的细胞内信号通路。Duox和吞噬细胞氧化酶Nox 2也是调节白细胞运输到肺部的主要候选者。将体外分化的人肺上皮细胞和分离的人中性粒细胞组合在模型系统中，该模型系统允许遗传操作和通过免疫荧光和电子显微镜观察结构变化。我们的研究将表明氧化酶是否是治疗药物开发的一个有前途的靶点。

Description (provided by applicant): Influenza A is a classic emerging disease. Genetic reassortment and/or adaptation to a new host can cause disastrous pandemics with high mortality. Influenza virus infects and replicates in the respiratory epithelium and induces inflammatory infiltrates comprised of neutrophils and monocytes. The primary innate immune response is initiated at the apical surface of the airway epithelium, at a location where a recently identified NADPH oxidase, Duox, resides. Duox generates reactive oxygen species, and has been implicated in wound healing and in changes of the pH and redox environment. These features position Duox as an ideal participant in the local immune response during airborne microbial pathogenesis. This project uses forward genetics to elucidate how Duox proteins regulate intracellular signaling pathways essential for anti-viral host defense. Duox and the phagocyte oxidase Nox2 are also prime candidates for regulating leukocyte trafficking into the lungs. An in vitro differentiated human lung epithelium and isolated human neutrophils will be combined in a model system that permits genetic manipulation and visualization of structural changes by immunofluorescence and electron microscopy. Our studies will show if oxidases are a promising target for therapeutic drug development.