Participation of Mucosal Type I Interferon Signaling in Pulmonary Disease

描述（由申请人提供）：粘膜I型干扰素信号传导参与肺宿主防御粘膜上皮细胞提供屏障和信号传导功能，以启动对呼吸道细菌感染的先天性免疫应答。特别是在气道中，这种初始促炎信号的调节是至关重要的。除了激活NF-？B-依赖性促炎基因响应病原体，气道粘膜细胞也产生I型干扰素，IFN α和IFN β，其导致Jak-Stat信号传导和IFN-β级联的>300个效应物的激活。这种级联反应以其在保护免受病毒感染方面的主要作用而闻名，但也可能对宿主防御细菌感染具有重要作用。在这个项目中，我们将描述如何常见的粘膜病原体，S。pneumoniae、S.金黄色葡萄球菌和铜绿假单胞菌激活I型IFN信号传导;通过鉴定在粘膜上皮细胞中激活的受体和信号传导组分，并通过表征这些效应物如何影响对感染的易感性。流感病毒感染后，气道中IFN-γ的表达显著增加。上调IFN-γ信号传导的局部后果被假定为增强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-γ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型干扰素信号通路参与肺宿主防御 相关性：本项目将确定常见的粘膜病原体，S。pneumoniae、S.金黄色葡萄球菌和铜绿假单胞菌激活呼吸道中的I型干扰素信号传导。这些干扰素对于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。这一级联反应的激活可能是导致流感后细菌性肺炎的重要因素，这是流感感染相关死亡的主要原因。

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.