Viral-Bacterial Interactions in the Airway Epithelium

气道上皮中的病毒-细菌相互作用

• 批准号: 6906061
• 负责人: RAYMOND J PICKLES
• 金额: $ 18.25万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6906061
• 关键词: Haemophilus influenzae; Paramyxovirus; Pseudomonas aeruginosa; bacteria infection mechanism; bacterial disease; clinical research; comorbidity; enzyme linked immunosorbent assay; fluorescence microscopy; green fluorescent proteins; microarray technology; pathologic process; respiratory airway pressure; respiratory epithelium; respiratory infections; respiratory syncytial virus; terminal nick end labeling; tissue /cell culture; transmission electron microscopy; virus cytopathogenic effect; virus diseases

DESCRIPTION (provided by applicant): It is well known that bacterial infections are often made worse by concurrent viral infections, a condition known as "bacterial superinfection". Infection of the human airways by specific viruses (e.g., influenza, respiratory syncytial virus (RSV) and parainfluenza virus (PIV) have been associated with bacterial pathogens such as non-typified Haemophilus influenzae (NTHi). The airways of cystic fibrosis patients are often colonized by Pseudomonas aeruginosa at similar times that these patients are also susceptible to respiratory viruses although the association between the two pathogen-types is less well documented. Potential mechanisms proposed to result in bacterial super infection include: viral-induced alteration of innate immune systems; reduced mucociliary clearance; the accumulation of excess/altered airway secretions; and, reduced activity of phagocytotic cell-types. Evidence also exists for viral-induced up-regulation of bacterial adherence receptors on epithelial cells. We propose to use an in vitro model of human ciliated airway epithelial cells (HAE) that display many of the physiological functions of the airway epithelium in vivo to perform systematic and quantitative analyses of the effect of viral infection on bacterial superinfection. For these studies we have chosen RSV and PIV3 since we are confident that we can infect HAE with these viruses and maintain the cultures for extended periods post-inoculation. We will attempt to determine the mechanisms that are altered by these viruses that may lead to superinfection by NTHI and PA. We propose the following Specific Aims: 1) Does viral-infection of human ciliated cells promote early bacterial interactions with the airway surface microenvironment? 2) To determine the patho-physiological consequences of viral-infection of ciliated cells that result in bacterial superinfection. 3) To identify potential bacterial attachment factors that are up-regulated by viral-Infection. Elucidation of the processes/molecules that may be altered by viral infection may give insight into new therapeutic targets to limit these effects and thus reduce the pathology associated with bacterial superinfection. The novel aspect of these studies are the bringing together of methods to measure physiological and molecular changes induced by viruses in a single model system that accurately resembles the cell-type distribution of the human airway epithelium.

描述（由申请人提供）：众所周知，细菌感染通常会因并发病毒感染而恶化，这种情况称为“细菌重叠感染”。特定病毒感染人体气道（例如，流感、呼吸道合胞病毒（RSV）和副流感病毒（PIV）与细菌病原体如非典型流感嗜血杆菌（NTHi）有关。囊性纤维化患者的气道通常被铜绿假单胞菌定殖，这些患者也对呼吸道病毒易感，尽管这两种病原体类型之间的相关性记录较少。提出的导致细菌超级感染的潜在机制包括：病毒诱导的先天免疫系统改变;粘膜纤毛清除减少;过量/改变的气道分泌物积累;以及吞噬细胞类型的活性降低。也存在病毒诱导的上皮细胞上细菌粘附受体上调的证据。我们建议使用一个体外模型的人纤毛气道上皮细胞（HAE），显示许多的生理功能的气道上皮细胞在体内进行系统和定量分析的影响病毒感染细菌的双重感染。为 在这些研究中，我们选择了RSV和PIV 3，因为我们相信我们可以用这些病毒感染HAE。 病毒，并在接种后延长培养时间。我们将试图确定这些病毒改变的可能导致NTHI和PA双重感染的机制。我们提出以下具体目的：1）病毒感染人类纤毛细胞是否促进早期细菌与气道表面微环境的相互作用？2)确定病毒感染纤毛细胞导致细菌重复感染的病理生理后果。3)鉴定受病毒感染上调的潜在细菌附着因子。阐明可能被病毒感染改变的过程/分子可以深入了解新的治疗靶点，以限制这些作用，从而减少与细菌重复感染相关的病理学。这些研究的新方面是将测量由病毒诱导的生理和分子变化的方法结合在一起，该方法在单个模型系统中准确地类似于人类气道上皮的细胞类型分布。