Collectins and Innate Defense against Inhaled Pathogens

该计划项目的中心主题是了解宿主的先天防御机制 吸入的病原体由两种肺集合素、表面活性蛋白A和D（SP-A、SP-D）组成。这个 了解不仅对于流行的呼吸道感染很重要，而且对于那些 与严重的全球生物威胁相关——抗生素抗药性生物体的出现；进化和 更致命的呼吸道病毒迅速传播；以及吸入病原体在行动中的潜在用途 生物恐怖主义。有效的肺部宿主防御需要早期识别微生物。正在关注 当有机体沉积到呼吸道时，病原体有一个关键的机会窗口 清关；延迟反应有利于感染。肺集合素在先天性中发挥着前线作用 防御许多革兰氏阴性和阳性细菌及其内毒素、分枝杆菌、致病菌 真菌和专性细胞内病原体，包括甲型流感 (LAV) 和其他潜在致命病毒。 肺集合素的先天防御特性取决于它们的快速识别，并且在某些情况下 基于高度保守微生物模式识别的吸入微生物中和案例 表面成分，例如 LAV 上的 N 连接高甘露糖聚糖和革兰氏阴性脂多糖 （内毒素）。其他研究表明，缺乏肺集合素的动物表现出显着增加 对微生物挑战的敏感性。重组截短型 SP-A 和 SP-D 在小鼠体内的研究 过敏和感染模型提供了这些蛋白质的雾化形式递送的可能性 吸入可能具有控制呼吸道感染、炎症和过敏的治疗潜力 人类。在这个项目中，一个高度协作和重点突出的项目组使用互补的 方法，包括 X 射线晶体学、诱变、光谱学、体外和体内分析 动物模型，专门针对集合素和调节蛋白质（例如 KGF）的先天反应 它们对 LAV 和革兰氏阴性细菌的活性，以获得机制理解并协助设计 潜在的基于集合素的疗法，具有增强的抗菌活性。 。

The central theme of the Program Project is to understand the innate host defense mechanisms against inhaled pathogens by the two pulmonary collectins, surfactant proteins A and D (SP-A, SP-D). This understanding is important not only in the context of prevalent respiratory infections but also those associated with serious global biothreats ¿ the emergence of antibiotic-resistant organisms; evolution and rapid spread of more lethal respiratory viruses; and potential use of inhaled pathogens in acts of bioterrorism. Effective pulmonary host defense requires early recognition of microorganisms. Following deposition of an organism into the respiratory tract, there is a critical window of opportunity for pathogen clearance; delayed response favors infection. The pulmonary collectins play a front-line role in the innate defense against many gram-negative and positive bacteria and their endotoxins, mycobacteria, pathogenic fungi, and obligate intracellular pathogens including influenza A (lAV) and other potentially lethal viruses. The innate defense properties of pulmonary collectins depend upon their rapid recognition and, in some cases, neutralization of inhaled microorganisms based on pattern recognition of highly-conserved microbial surface components such as N-linked high-mannose glycans on lAV and gram-negative lipolysaccharide (endotoxin). Other studies show that animals deficient in lung collectins show significantly increased susceptibility to microbiological challenges. Studies of recombinant truncated SP-A and SP-D in murine models of allergy and infection have offered the possibility that aerosolized forms of these proteins delivered by inhalation may have therapeutic potential in controlling respiratory infection, inflammation, and allergy in humans. In this program project, a highly collaborative and focused group of projects using complementary approaches, including x-ray crystallography, mutagenesis, spectroscopy, in vitro and in vivo analyses using animal models, aim specifically at innate responses of collectins, and proteins such as KGF that modulate their activity, to lAV and gram-negative bacteria both to gain mechanistic understanding and assist design of potential collectin-based therapeutics with increased antimicrobial activities. .