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

IL-33 在流感和金黄色葡萄球菌合并感染中的作用

基本信息

批准号：
9320979
负责人：
Keven Mara Robinson
金额：
$ 16.07万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9320979
关键词：
Acute Acute Lung Injury Advisory Committees Affect Animal Model Animals Area Attenuated Bacteria Bacterial Infections Bacterial Pneumonia Cells Cessation of life Chronic Clinical Communication Data Development Educational process of instructing Environment Epithelial Epithelial Cells Family Flow Cytometry Funding Future Gene Expression Goals Grant Histology Host Defense Human Immune Immune Targeting Immune system Immunologics Immunology Impairment In Situ Hybridization Infection Inflammatory Influenza Influenza A virus Injury Interleukin-1 Interleukin-13 Interleukin-5 Laboratories Leadership Learning Lung Lymphoid Tissue Measures Mentors Mentorship Messenger RNA Molecular Morbidity - disease rate Mus Myeloid Cells Pathogenesis Pathway interactions Phenotype Physicians Physiological Physiology Pneumonia Population Positioning Attribute Predisposition Production Protein Isoforms Pulmonary function tests RNA analysis Reporter Research Research Personnel Research Project Grants Resources Respiratory physiology Reverse Transcriptase Polymerase Chain Reaction Role Scientist Secondary to Signal Pathway Signal Transduction Skin Staphylococcus aureus Streptococcus pneumoniae Techniques Testing Therapeutic Therapeutic Intervention Tissues Training Translating United States National Institutes of Health Universities Virus Diseases Writing adaptive immune response arginase attenuation base career career development co-infection cytokine experience experimental study human disease inhibitor/antagonist killings knowledge base lung injury lung repair macrophage mortality new therapeutic target novel therapeutic intervention prevent receptor repaired respiratory respiratory virus response skills superinfection symposium therapeutic target tool transcriptome sequencing translational study uptake

项目摘要

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.

项目摘要流感是一种常见的呼吸系统疾病，每年在全球范围内最多可死亡500,000人死亡。流感a 感染通常会因肺的继发细菌感染而复杂，例如金黄色葡萄球菌（SA）或肺炎链球菌。我们的长期目标是开发新颖的治疗干预措施临床环境可预防与流感相关的次生细菌性肺炎的发病率和死亡率。经过确定相关的细胞信号通路，这些研究有可能引入新的治疗性目标。 IL-1细胞因子促进促炎的先天和适应性免疫反应。 IL-33是新的在上皮屏障组织和淋巴组织和刺激2型免疫细胞的发展。另外，IL-33可以移动巨噬细胞极化朝着替代激活的巨噬细胞（M2A）表型。根据我们的初步数据，我们假设IL-33对于SA宿主防御至关重要，而在感染之前，IL-33损害了IL-33 依赖的巨噬细胞功能，导致软管防御对SA的衰减和肺部加剧受伤。研究目的：1）检验以下假设：上皮细胞得出的IL-33对于SA宿主至关重要防御2）检验IL-33促进M2A巨噬细胞极化并增强的假设流感/SA共感染期间的巨噬细胞功能，3）检验了流感/SA共同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的失调流感感染和外源IL-33后的上皮修复会减轻上皮损害。这候选人的长期职业目标是成为NIH资助的独立医师科学家肺部的托管防御。直接的职业发展目标包括：1）发展专业知识免疫，细胞和分子生物学技术，2）发展技能以翻译细胞的发现，分子和动物研究人类疾病，3）精通肺部评估动物模型中的生理学，4）增强沟通和领导能力。拟议的培训计划将为候选人提供扩大知识基础以包括高级的机会免疫学和生理技术。通过直接在实验室，课程和会议，候选人将获得流式细胞仪的高级培训，原位杂交，RNA 测序，使用弹性进行肺功能测试以及授予写作/表现/领导能力。这导师博士的资源和专业知识。 Alcorn和Kolls结合了候选人的科学咨询匹兹堡大学委员会和丰富的研究环境确保候选人的成功过渡到独立研究者。