Role of IL-33 in Influenza and Staphylococcus aureus Co-infection

项目摘要 流感是一种常见的呼吸道疾病，每年在全世界造成多达50万人死亡。甲型流感 感染通常并发肺部继发性细菌感染，如金黄色葡萄球菌 (SA)或肺炎链球菌。我们的长期目标是开发新的治疗干预措施， 预防流感相关继发性细菌性肺炎的发病率和死亡率的临床环境。通过 通过识别相关的细胞信号通路，这些研究有可能引入新的治疗方法， 目标的IL-1细胞因子促进促炎性先天性和适应性免疫应答。IL-33是一种新的 在上皮屏障组织和淋巴组织中表达的IL-1家族中鉴定的细胞因子， 刺激2型免疫细胞的发育。此外，IL-33可以改变巨噬细胞极化， 朝向交替活化的巨噬细胞（M2a）表型。根据初步数据，我们 假设IL-33对SA宿主防御至关重要，并且之前的甲型流感感染会损害IL-33 依赖性巨噬细胞功能，导致对SA的软管防御减弱和肺损伤加重。 损伤研究目的：1）验证上皮细胞来源的IL-33对SA宿主的免疫调节作用 防御2）为了检验IL-33促进M2a巨噬细胞极化并增强M2a巨噬细胞的增殖的假设， 流感/SA共感染期间巨噬细胞功能，以及3）为了检验流感/SA共感染的假设， 感染导致急性和慢性上皮损伤，肺功能受损，以及正常呼吸系统功能失调。 流感病毒感染后上皮修复和外源性IL-33可减轻上皮损伤。的 候选人的长期职业目标是成为一个独立的NIH资助的医生科学家在该地区 肺的宿主防御近期职业发展目标包括：1）发展以下方面的专业知识 免疫学、细胞学和分子生物学技术，2）培养从细胞中翻译结果的技能， 分子和动物研究人类疾病，3）成为熟练的评估肺 动物模型的生理学，以及4）提高沟通和领导技能。拟议的培训 计划将为候选人提供机会，以扩大她的知识基础，包括先进的 免疫学和生理学技术。通过实验室的直接教学，课程和 会议，候选人将获得先进的培训，在流式细胞术，原位杂交，RNA 排序，使用flexiVent进行肺功能测试，并授予写作/演讲/领导技能。的 导师奥尔康博士和科尔斯博士的资源和专业知识与候选人的科学咨询相结合 委员会和匹兹堡大学丰富的研究环境保证了候选人的成功 过渡到独立调查员。

PROJECT SUMMARY Influenza is a common respiratory illness that results in up to 500,000 deaths worldwide each year. Influenza A infection is often complicated by secondary bacterial infections of the lung, such as Staphylococcus aureus (SA) or Streptococcus pneumoniae. Our long-term goal is to develop novel therapeutic interventions for use in clinical settings to prevent morbidity and mortality from influenza-related secondary bacterial pneumonia. By identifying relevant cell signaling pathways, these studies have the potential to introduce novel therapeutic targets. IL-1 cytokines promote pro-inflammatory innate and adaptive immune responses. IL-33 is a newly identified cytokine in the IL-1 family that is expressed in epithelial barrier tissues and lymphoid tissues and stimulates the development of Type 2 immune cells. In addition, IL-33 can shift macrophage polarization towards an alternatively activated macrophage (M2a) phenotype. Based on our preliminary data, we hypothesize that IL-33 is essential to SA host defense and that preceding influenza A infection impairs IL-33 dependent macrophage function, resulting in attenuation of hose defense against SA and exacerbation of lung injury. Research aims: 1) To test the hypothesis that epithelial cell derived IL-33 is essential to SA host defense 2) To test the hypothesis that IL-33 promotes M2a macrophage polarization and enhances macrophage function during influenza/SA co-infection, and 3) To test the hypothesis that influenza/SA co- infection leads to acute and chronic epithelial injury, impaired lung function, and dysregulation of normal epithelial repair following influenza infection and that exogenous IL-33 can alleviate epithelial damage. The candidate's long term career goal is to become an independent NIH-funded physician scientist in the area of host defense of the lung. Immediate career development objectives include: 1) To develop expertise in immunologic, cellular, and molecular biologic techniques, 2) To develop skills to translate findings from cellular, molecular and animal studies into human disease, 3) To become proficient in the assessment of pulmonary physiology in animal models, and 4) To enhance communication and leadership skills. The proposed training plan will provide the candidate with the opportunity to expand her knowledge base to include advanced immunologic and physiologic techniques. Through direct teaching in the laboratory, coursework and conferences, the candidate will acquire advanced training in flow cytometry, in situ hybridization, RNA sequencing, use of flexiVent for lung function testing, and grant writing/presentation/leadership skills. The resources and expertise of mentors Drs. Alcorn and Kolls combined with the candidate's scientific advisory committee and the rich research environment at the University of Pittsburgh assure the candidate's successful transition to an independent investigator.