Host-Pathogen Interactions in the Mammalian Airway

描述（由申请方提供）：哺乳动物气管内衬的上皮细胞是宿主防御空气微生物病原体的关键部位，释放多种抗菌因子。这些防御的缺陷可能导致反复的气道感染。这些防御机制之一是β-防御素的诱导产生，β-防御素是一类在哺乳动物上皮细胞中高度丰富的同源抗生素肽。编码β-防御素的基因在呼吸道上皮中以高水平表达，并且由细菌产物和炎症介质诱导。初步和已发表的数据支持这样的假设，即一些致病性细菌菌株可以通过抑制β-防御素基因表达来逃避气道中的先天免疫系统，这反过来又可以减少气道的抗菌防御。特异性细菌毒力因子允许逃避宿主第一道防线而定殖于气道的机制尚未确定。阐明这些机制将有助于气道感染治疗策略的发展。我们研究的长期目标是更好地了解气道中的动态宿主防御系统。在这个建议中，我们专注于呼吸道病原体，支气管败血波氏杆菌与其在呼吸道上皮细胞的靶细胞的相互作用。B。支气管败血症与动物的呼吸道感染有关，并且与B密切相关。百日咳是人类百日咳的病原体。我们假设气道上皮细胞通过识别特定受体的分子模式对细菌作出反应，从而激活NF-κ B并诱导β-防御素基因表达以防止定植。B.支气管败血症可以通过经由III型分泌因子干扰抗微生物肽基因的上调来防止抗微生物肽的产生增加，所述III型分泌因子干扰先天免疫应答。为了验证这些假设，提出了以下目标：1。定义B的交互作用。支气管败血症与气道上皮细胞的关系以及由此引起的先天性免疫应答的诱导。2.明确强毒B抑制天然免疫诱导的机制。支气管炎这些研究的目的是确定气道上皮细胞如何通过启动宿主防御反应来响应该模型病原体。第二个目标将确定细菌如何利用蛋白质组学来识别负责这种行为的细菌因子，以及该因子与防御反应相互作用的全面表征来规避这种反应。这些信息将作为开发用于呼吸道的新疗法的基础。这将包括调节内源性抗微生物肽表达以预防严重细菌感染的策略。

DESCRIPTION (provided by applicant): Epithelial cells lining the mammalian trachea form a crucial site in the host defense against airborne microbial pathogens, releasing numerous antimicrobial factors. Deficiencies in these defenses may result in recurrent airway infections. One of these defense mechanisms is the inducible production of beta-defensins, a class of homologous antibiotic peptides highly abundant in mammalian epithelial cells. The genes encoding beta-defensins are expressed at high levels in the respiratory epithelium, and are induced by bacterial products and inflammatory mediators. Preliminary and published data support the hypothesis that some pathogenic strains of bacteria can evade the innate immune system in the airway by inhibiting beta-defensin gene expression, which can in turn diminish the antimicrobial defense of the airway. The mechanisms by which the specific bacterial virulence factors allow evasion of the first lines of host defense to colonize the airway are not yet defined. Elucidation of these mechanisms will aid in the development of therapeutic strategies for airway infections. The long-range goal of our research is to better understand the dynamic host defense systems in the airway. In this proposal we focus on the interactions of the airway pathogen, Bordetella bronchiseptica with its target cells in the respiratory epithelium. B. bronchiseptica is associated with respiratory infections in animals, and is closely related to B. pertussis, the causative agent of whooping cough in humans. We hypothesize that airway epithelial cells respond to bacteria by recognition of molecular patterns by specific receptors, resulting in the activation of NF-kappaB and induction of beta-defensin gene expression in order to prevent colonization. Pathogenic strains of B. bronchiseptica can prevent the increased production of antimicrobial peptides by interfering with the upregulation of the antimicrobial peptide genes through a type III secretion factor which interferes with the innate immune response. To test these hypotheses, the following aims are proposed: 1. Define the interaction of B. bronchiseptica with airway epithelial cells and the resultant induction of an innate immune response. 2. Define the mechanism of inhibition of innate immune induction by virulent B. bronchiseptica. The objective of these studies is to define how the airway epithelium responds to this model pathogen by the initiation of a host defense response. The second aim will determine how the bacterium circumvents this response utilizing proteomics to identify the bacterial factor responsible for this action, as well as a comprehensive characterization of the interaction of this factor and the defense response. The information will serve as a foundation for the development of novel therapies designed to work in the respiratory tract. This would include strategies to modulate the endogenous antimicrobial peptide expression to prevent serious bacterial infections.