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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：
10682497
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/10682497
关键词：
Acute Address Antiviral Therapy Attenuated Bacterial Infections Bacterial Pneumonia Bicarbonates Chemosensitization Clinical Cystic Fibrosis Transmembrane Conductance Regulator Data Disease Epithelium 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 Methodology Modeling Molecular Mus Pathogenesis Pharmaceutical Preparations Play Pneumococcal Infections Pneumonia Positioning Attribute Predisposition Prevention Prophylactic treatment Proteins Publishing Regulation Respiratory System Role Secondary to Sepsis Streptococcus pneumoniae Surface Testing Tissues 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 pharmacologic 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.

项目总结