Participation of Mucosal Type I Interferon Signaling in Pulmonary Disease

粘膜 I 型干扰素信号转导参与肺部疾病

基本信息

批准号：
7706229
负责人：
Alice S Prince
金额：
$ 23.51万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7706229
关键词：
Affect Anti-Inflammatory Agents Anti-inflammatory Bacterial Infections Bacterial Pneumonia CXCL10 gene Cell physiology Cells Dendritic Cells Epithelial Epithelial Cells Genes Host Defense IFNAR1 gene ITGAX gene Immune Immune response Infection Inflammatory Influenza Interferon Type I Interferons Interleukin-6 LIF gene Lung Lung diseases Modeling Morbidity - disease rate Mus PTPN11 gene Pathogenesis Phagocytes Phosphorylation Physiological Play Predisposition Production Pseudomonas aeruginosa Receptor Signaling Recruitment Activity Regulation Respiratory Mucosa Respiratory System Respiratory tract structure Role Secondary to Signal Transduction Staphylococcus aureus Streptococcus pneumoniae Testing Viral Virus Diseases chemokine cytokine influenzavirus microbial mortality mutant pathogen protective effect research study respiratory response superinfection

项目摘要

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.

描述（由应用提供）：粘膜I型干扰素信号在肺部防御粘膜上皮细胞中的参与提供屏障和信号传导功能，以引发对呼吸道中细菌感染的先天免疫回报。在气道中，这种初始促炎信号的调节至关重要。除了激活NF-依赖性促炎基因对病原体的响应外，气道粘膜细胞还会产生I型干扰素，IFNS A和¿该级联反应以保护病毒感染的主要作用而闻名，但也可能对宿主防御对细菌感染产生重要影响。在这个项目中，我们将表征常见的粘膜病原体，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成分，并表征这些作用如何影响感染的易感性。响应影响力的感染，气道中的IFN- - 表达显着增加。更新的IFN-€信号传导的局部后果是为了增强对二次细菌感染的敏感性，这是影响与影响相关的死亡率的主要原因。这将在影响Za的鼠模型中进行测试，使用具有区分能力的影响力突变体刺激IFN-€的产生并比较它们如何影响细菌超级感染的易感性。我们预测，粘膜上皮产生的产生，通过激活肺树突状细胞的作用可能会增加宿主对常见细菌病原体感染的易感性。 I型I型干扰素信号在肺部宿主防御中的参与相关性：该项目将确定如何在呼吸道中激活I型干扰素信号的常见粘膜病原体，肺炎链球菌，金黄色葡萄球菌和铜绿假单胞菌。这些干扰素对于有效的抗病毒防御措施至关重要，但似乎增加了对细菌感染的敏感性。该级联反应的激活可能是导致肺炎后肺炎后的重要因素，这是与影响力感染相关的死亡率的主要原因。