Participation of Mucosal Type I Interferon Signaling in Pulmonary Disease

描述（由申请人提供）：参与肺宿主防御的粘膜I型干扰素信号传递，粘膜上皮细胞提供屏障和信号传递功能，启动呼吸道细菌感染的先天免疫反应。特别是在气道中，对这种初始促炎信号的调节至关重要。除了激活NF-？在对病原体的反应中，b依赖的促炎基因，气道粘膜细胞也产生I型干扰素，ifna和¿，导致Jak-Stat信号和IFN-¿级联的bbb300效应物的激活。这个级联最为人所知的是它在防止病毒感染方面的主要作用，但也可能对宿主防御细菌感染也有重要作用。在这个项目中，我们将描述常见的粘膜病原体，肺炎链球菌，金黄色葡萄球菌和铜绿假单胞菌如何激活I型IFN信号；通过识别粘膜上皮细胞中激活的受体和信号成分，并通过表征这些效应器如何影响对感染的易感性。IFN-¿在流感感染后气道中的表达显著增加。据推测，IFN-¿信号上调的局部后果会增加对继发性细菌感染的易感性，而继发性细菌感染是流感相关死亡的主要原因。这将在小鼠流感模型中进行测试，使用具有不同能力的流感突变体刺激IFN-¿的产生，并比较它们如何影响对细菌重复感染的易感性。我们预测粘膜上皮IFN-¿的产生，可能通过激活肺树突状细胞的作用，增加宿主对常见细菌病原体感染的易感性。粘膜I型干扰素信号在肺宿主防御中的参与

DESCRIPTION (provided by applicant): Participation of mucosal type I interferon signaling in pulmonary host defenses mucosal epithelial cells provide both barrier and signaling functions to initiate innate immune responses to bacterial infection in the respiratory tract. Particularly in the airways, the regulation of this initial proinflammatory signaling is critical. In addition to activating NF-?B-dependent proinflammatory genes in response to pathogens, airway mucosal cells also produce type I interferons, IFNs a and ¿ which result in Jak-Stat signaling and the activation of >300 effectors of the IFN-¿ cascade. This cascade is best known for its major role in protection from viral infection, but is likely to have important effects on host defense against bacterial infection as well. In this project we will characterize how common mucosal pathogens, S. pneumoniae, S. aureus and P. aeruginosa activate type I IFN signaling; by identifying the receptors and signaling components that are activated in mucosal epithelial cells and by characterizing how these effectors affect susceptibility to infection. IFN-¿ expression is significantly increased in the airways in response to influenza infection. The local consequences of upregulated IFN-¿ signaling are postulated to enhance susceptibility to secondary bacterial infection, the major cause of influenza- associated mortality. This will be tested in a murine model of influenza, using influenza mutants with differing abilities to stimulate IFN-¿ production and comparing how they affect susceptibility to bacterial superinfection. We predict that mucosal epithelial IFN-¿ production, possibly through effects in activating pulmonary dendritic cells, increases host susceptibility to infection by common bacterial pathogens. Participation of mucosal type I interferon signaling in pulmonary host defenses RELEVANCE: This project will establish the how common mucosal pathogens, S. pneumoniae, S. aureus and P. aeruginosa activate type I interferon signaling in the respiratory tract. These interferons are critical for effective anti-viral defenses but appear to increase susceptibility to bacterial infection. Activation of this cascade may be an important factor contributing to post-influenza bacterial pneumonia, the major cause of mortality associated with influenza infection.