Viral-Bacterial Interactions in the Airway Epithelium

气道上皮中的病毒-细菌相互作用

基本信息

批准号：
7068510
负责人：
RAYMOND J PICKLES
金额：
$ 17.82万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2008-05-31
项目状态：
已结题

项目摘要

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，细菌感染常常因并发的病毒感染而变得更糟，这种情况被称为“细菌二重感染”。人类呼吸道被特定病毒（例如流感、呼吸道合胞病毒（RSV）和副流感病毒（PIV））感染与细菌病原体（例如非典型流感嗜血杆菌（NTHi））有关。囊性纤维化患者的呼吸道通常铜绿假单胞菌定植的时间相似，这些患者也容易感染呼吸道病毒，尽管这两种病原体类型之间的关联尚不清楚。导致细菌过度感染的潜在机制包括：病毒诱导的先天免疫系统的改变；粘膜纤毛清除的减少；过量/改变的气道分泌物的积累；以及病毒诱导的吞噬细胞类型的活性降低。我们建议使用人纤毛气道上皮细胞（HAE）的体外模型，该模型显示出气道的许多生理功能。体内上皮细胞，对病毒感染对细菌重复感染的影响进行系统和定量分析。为了在这些研究中，我们选择了 RSV 和 PIV3，因为我们有信心可以用这些病毒感染 HAE 病毒并在接种后长时间维持培养物。我们将尝试确定这些病毒改变的可能导致 NTHI 和 PA 重复感染的机制。我们提出以下具体目标：1）人类纤毛细胞的病毒感染是否会促进早期细菌与气道表面微环境的相互作用？ 2) 确定纤毛细胞病毒感染导致细菌重复感染的病理生理学后果。 3) 识别病毒感染上调的潜在细菌附着因子。阐明病毒感染可能改变的过程/分子可以深入了解新的治疗靶点，以限制这些影响，从而减少与细菌重复感染相关的病理。这些研究的新颖之处在于，将测量病毒引起的生理和分子变化的方法汇集到一个模型系统中，该系统准确地模拟了人类气道上皮的细胞类型分布。