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Influenza regulation of epithelial pneumococcal host defense.

上皮性肺炎球菌宿主防御的流感调节。

基本信息

批准号：
10260454
负责人：
Kevin S Harrod
金额：
$ 37.13万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-10 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10260454
关键词：
Acute Address Antiviral Therapy Attenuated Bacterial Infections Bacterial Pneumonia Bicarbonates Chemosensitization Clinical Cystic Fibrosis Transmembrane Conductance Regulator Data Disease Epithelial Experimental Models FDA approved FluMist Functional disorder Goals Grant Health Heart Diseases Hospitalization Host Defense Human Immunologics In Vitro Infection Influenza Influenza A virus International Intervention Investigation Ion Channel Ions Iron Kidney Diseases Knowledge Laboratories Lead Link Liquid substance Lung Lung infections Mediating Mediator of activation protein Methodology Modeling Molecular Mus Pathogenesis Pharmaceutical Preparations Pharmacology Play Pneumococcal Infections Pneumonia Positioning Attribute Predisposition Prevention Prophylactic treatment Proteins Publishing Regulation Respiratory System Role Secondary to Sepsis Streptococcus pneumoniae Surface Testing Tissues Vaccine Therapy Vaccines Virus Diseases airway epithelium airway surface liquid bactericide co-infection cofactor endoplasmic reticulum stress experimental study global health health disparity healthy volunteer human disease human model in vivo in vivo Model influenza infection mouse model novel pathogenic bacteria secondary infection translational study

项目摘要

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.

项目概要尽管有全球监测、有效的疫苗和疫苗，流感感染仍然是一个国际健康问题抗病毒治疗。继发性细菌感染正在成为人类疾病的重要原因流感，然而，关于流感如何增加细菌感染的易感性，人们知之甚少。肺炎球菌感染是流感后继发细菌感染的最常见原因，并且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中。我们对继发性肺炎球菌感染的认识存在重大差距，但差距并不大比流感后肺上皮在细菌宿主防御中的作用。该应用程序将从机制上解构流感如何增强肺部肺炎球菌感染的易感性上皮细胞，并将填补我们目前关于流感继发细菌知识的重要空白感染。我们实验室在实验性肺部感染和原代分化肺上皮方面的专业知识文化模型使我们在这项调查中处于独特的地位。这里我们提出三个机械驱动的已发表的初步数据支持的目标明确支持我们的科学前提，即流感- 上皮离子失调的驱动变化导致气道表面液体酸化，从而增强对肺炎球菌感染的易感性。具体来说，目标 1 将阐明肺上皮的关键作用流感后易患肺炎球菌。目标 2 将机械地测定上皮离子导致气道上皮表面液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传播肺外疾病，同时探索 FDA 批准药物的重新用途的干预措施。总的来说，该提案将为流感介导的疾病提出一种全新的潜在机制。对肺炎球菌感染的易感性，将建立人体实验模型来研究流感- 肺炎球菌合并感染，并评估可快速实施的药物干预措施预防继发性肺炎球菌感染流感。