Innate immune-mediated control of pulmonary Legionella pneumophila infection

先天免疫介导控制肺部嗜肺军团菌感染

基本信息

批准号：
9180679
负责人：
Sunny Shin
金额：
$ 40万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-11-16 至 2020-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9180679
关键词：
AIDS Vaccines Alveolar Macrophages Anti-Bacterial Agents Antibiotic Resistance Bacterial Infections Cells Communities Community Hospitals Data Defense Mechanisms Development Ensure Epithelial Cells Epithelium Family Future Genetic Host Defense Host Defense Mechanism Immune Immune response Immune signaling Immunity In Vitro Individual Infection Infection Control Inflammatory Inflammatory Response Injectable Innate Immune System Interleukin-1 Interleukin-1 alpha Interleukin-1 beta Interleukin-12 Interleukin-18 Interleukin-6 Knowledge Legionella Legionella pneumophila Legionnaires&apos Disease Lung Mediating Molecular Morbidity - disease rate Mus Neutrophil Infiltration Nosocomial pneumonia Outcome Pathway interactions Pneumonia Production Protein Biosynthesis Proteins Publishing Research Role Signal Transduction TNF gene Testing Therapeutic Toll-like receptors Type IV Secretion System Pathway Vaccine Design Vaccines Virulence Virulence Factors alveolar epithelium antimicrobial base cell type chemokine cytokine design immune clearance immune function improved insight interleukin-18 receptor microbial mortality mouse model neutrophil novel novel strategies paracrine pathogen public health relevance release factor response

项目摘要

DESCRIPTION (provided by applicant): Clearance of intracellular bacterial pathogens requires initiation of an effective immune response. However, pathogens have evolved virulence factors to disable such immune responses. A key gap in our knowledge is to understand how successful host defense can be achieved despite pathogen subversion. Legionella pneumophila, an important cause of community- and hospital-acquired pneumonia, disarms and replicates within alveolar macrophages by delivering bacterial effectors via a type IV secretion system (T4SS). Several T4SS effectors potently block host protein synthesis. However, host sensing of Legionella T4SS-translocated substrates paradoxically enhances cytokine production. To elucidate the molecular and cellular basis of this host response, we developed a powerful approach to simultaneously track bacterial effector translocation and cytokine responses at the single cell level. We found that infected cells poorly produced several key cytokines, but could still synthesize and release IL-1 family cytokines. Moreover, IL-1 signaling was required for robust production of cytokines by uninfected immune cells and neutrophil-attracting chemokines by lung epithelial cells. Our findings indicate that paracrine IL-1 signaling circumvents the pathogen-imposed translational block to orchestrate a rapid immune response by uninfected bystander cells. While IL-1 signaling is critical for the initiation of host defense,the cell types responding to IL-1 and the specific consequences of IL-1α and IL-1β responses in these cells are unclear. Moreover, mice lacking IL-1 signaling eventually recover bystander cytokine responses, neutrophil recruitment, and control over infection, suggesting that IL-1-independent immune signals coordinate an additional layer of host defense. Thus, we propose the following Aims to define how IL-1-dependent and IL-1-independent immune mechanisms collaborate to generate successful immunity. In Aim 1, we will test the hypothesis that IL-1α and IL-1β regulate distinct immune functions in different cell types. In Aim 2, we will test the hypothesis that additional IL-1-independent immune signals ensure bystander cytokine production and neutrophil recruitment at later stages of Legionella infection. Together, these studies will define novel innate immune mechanisms employed by the host to surmount pathogen-encoded virulence activities. The proposed research will therefore provide vital insight into mechanisms of host defense that are utilized against broad classes of microbial pathogens and aid development of improved anti-microbial therapeutics and vaccines.

描述（适用提供）：细胞内细菌病原体的清除率需要有效的免疫响应。然而，病原体已经进化了病毒因子以禁用这种免疫响应。我们知识上的一个关键差距是了解如何成功实现宿主防御。肺炎军团菌是社区和医院获得的肺炎的重要原因，通过通过IV型分泌系统（T4SS）传递细菌效应子，在肺泡巨噬细胞中解除武装和复制。几种T4SSSSSSSSS可能会阻止宿主蛋白质合成。然而，宿主T4SS转移的底物的宿主传感矛盾地增强了细胞因子的产生。为了阐明该宿主反应的分子和细胞基础，我们开发了一种强大的方法，可以简单地在单细胞水平跟踪细菌效应子易位和细胞因子反应。我们发现感染细胞产生的细胞不足，但仍可以合成并释放IL-1家族细胞因子。此外，未感染的免疫细胞和肺上皮细胞吸引嗜中性粒细胞趋化因子需要IL-1信号传导才能强化细胞因子。我们的发现表明旁分泌IL-1信号传导绕过病原体施加的翻译阻滞，以协调未感染的旁观者细胞快速免疫响应。尽管IL-1信号对于宿主防御的倡议至关重要，但对IL-1响应的细胞类型以及这些细胞中IL-1α和IL-1β反应的特定后果尚不清楚。此外，缺乏IL-1信号传导的小鼠最终恢复了旁观者的细胞因子反应，中性粒细胞的募集以及对感染的控制，这表明IL-1非依赖性免疫信号协调了额外的宿主防御层。这就是我们提出以下旨在定义IL-1依赖性和IL-1独立的免疫机制如何协作以生成成功的免疫组织化学物质。在AIM 1中，我们将检验以下假设：IL-1α和IL-1β调节不同细胞类型中不同的免疫素功能。在AIM 2中，我们将检验以下假设：额外的IL-1非依赖性免疫信号可确保在军团菌感染的后期旁观者细胞因子的产生和中性粒细胞募集。总之，这些研究将定义宿主采用的新的先天免疫力学来克服病原体编码的病毒活性。因此，拟议的研究将提供对宿主防御机制的重要见解，宿主防御机制可用于针对广泛的微生物病原体，并有助于开发改善的抗微生物治疗和疫苗。