Participation of Mucosal Type I Interferon Signaling in Pulmonary Disease

描述(申请人提供)：粘膜I型干扰素信号在肺宿主防御中的参与粘膜上皮细胞提供屏障和信号功能，以启动对呼吸道细菌感染的先天免疫反应。尤其是在呼吸道，对这种最初的促炎信号的调节是至关重要的。除了激活依赖于核因子？B的致炎基因以响应病原体外，呼吸道粘膜细胞还产生I型干扰素，即干扰素α和干扰素β，从而导致Jak-Stat信号和干扰素-β级联反应的&gt；300效应器的激活。这种级联反应最为人所知的是它在预防病毒感染方面的主要作用，但也可能在宿主防御细菌感染方面发挥重要作用。在这个项目中，我们将通过识别粘膜上皮细胞中被激活的受体和信号成分，并通过表征这些效应因子如何影响感染的易感性，来表征常见的粘膜病原体，如肺炎链球菌、金黄色葡萄球菌和铜绿假单胞菌是如何激活I型干扰素信号的。流感感染后，呼吸道中干扰素-β的表达显著增加。据推测，干扰素信号上调的局部后果是增加了对继发性细菌感染的易感性，继发性细菌感染是流感相关死亡的主要原因。这将在流感的小鼠模型中进行测试，使用具有不同能力的流感突变株来刺激干扰素的产生，并比较它们如何影响细菌重叠感染的易感性。我们预测，粘膜上皮细胞产生的干扰素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。黏膜I型干扰素信号参与肺宿主防御 相关性：该项目将确定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呼吸道中的I型干扰素信号。这些干扰素对有效的抗病毒防御至关重要，但似乎会增加对细菌感染的易感性。这种级联反应的激活可能是导致流感后细菌性肺炎的一个重要因素，而细菌性肺炎是与流感感染相关的死亡的主要原因。

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.