Influenza regulation of epithelial pneumococcal host defense.

项目摘要 尽管有全球监测、有效的疫苗和 抗病毒治疗继发性细菌感染正在成为人类疾病的重要原因， 然而，关于流感如何增加对细菌感染的易感性知之甚少。 肺炎球菌感染是流感后继发性细菌感染的最常见原因， 肺外肺炎球菌感染正在成为急性心脏和肾脏疾病的主要原因 在人类身上。我们对继发性肺炎球菌感染的认识存在重大差距， 肺上皮在流感后细菌宿主防御中的作用。此应用程序将 从机制上解构流感如何增强肺部对肺炎球菌感染的易感性 上皮，并将填补我们目前关于流感继发性细菌的知识的重要空白 感染我们实验室在实验性肺部感染和原发性分化型肺上皮细胞 文化模式使我们在这项调查中处于独特的地位。在这里，我们提出了三个机械驱动的 目标得到已发表的初步数据的支持，这些数据明确支持我们的科学前提，即流感- 上皮细胞离子失调的驱动变化赋予气道表面流体酸化， 对肺炎球菌感染易感。具体来说，目标1将阐明肺上皮细胞的关键作用， 流感后对肺炎球菌的易感性。目的2将机械地确定上皮离子 导致气道上皮表面流体酸化的功能障碍是潜在的分子机制。 最后，目标3将阐明流感后体内肺炎球菌感染增加对肺炎的影响 和播散性肺外疾病，同时探索FDA批准的药物的干预措施。 总的来说，这一提议将提出一个全新的流感介导的潜在机制， 对肺炎球菌感染的易感性，将建立一个人类实验模型来研究流感- 肺炎球菌合并感染，并评估可以迅速实施的药物干预措施， 预防流感继发肺炎球菌感染。

PROJECT SUMMARY Influenza infection remains an international health concern despite global surveillance, effective vaccines, and antiviral therapy. Secondary bacterial infections are emerging as an important cause of human disease to influenza, however little is known regarding how influenza increases susceptibility to bacterial infection. Pneumococcal infection is the most common cause of secondary bacterial infection postinfluenza, and extrapulmonary pneumococcal infections are emerging as leading causes of acute cardiac and renal disease in humans. Significant gaps in our knowledge around secondary pneumococcal infection exists, none larger than the role of the lung epithelium in bacterial host defense following influenza. This application will mechanistically deconstruct how influenza enhances susceptibility to pneumococcal infection in the lung epithelium, and will fill important gaps in our current knowledge regarding influenza secondary bacterial infection. Our laboratory's expertise in experimental lung infection and primary differentiated lung epithelial culture models puts us uniquely positioned for this investigation. Here we put forth three mechanistically driven aims supported by published and preliminary data clearly supporting our scientific premise that influenza- driven changes in epithelial ion dysregulation confer airway surface fluid acidification that enhances susceptibility to pneumococcal infection. Specifically, Aim 1 will elucidate the critical role of the lung epithelium in susceptibility to pneumococci after influenza. Aim 2 will mechanistically determine epithelium ion dysfunction leading to acidification the airway epithelial surface fluid as the underlying molecular mechanism. Lastly, Aim 3 will elucidate the impact of increased pneumococcal infection postinfluenza in vivo in pneumonia and disseminated extrapulmonary disease, while exploring interventions of repurposed FDA approved drugs. Collectively, this proposal will put forth an entirely novel underlying mechanism for influenza-mediated susceptibility to pneumococcal infection, will establish a human experimental model to study influenza- pneumococcal coinfections, and evaluate pharmacologic interventions that could be implemented rapidly for prophylaxis to secondary pneumococcal infections to influenza.