Immunity to Pulmonary Infections

对肺部感染的免疫力

基本信息

批准号：
10692102
负责人：
Catharine Bosio
金额：
$ 131.17万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10692102
关键词：
Address Age Anti-Inflammatory Agents Attenuated Attenuated Vaccines Bacteria Bordetella pertussis Cause of Death Cell Death Cells Cessation of life Child Data Development Dose Elements Francisella Francisella tularensis Generations Genomics Goals Image Imaging technology Immune response Immunity Immunosuppression Impairment Individual Infection Infection prevention Infectious Agent Inflammation Inflammatory Response Klebsiella pneumoniae Lead Lipid Synthesis Pathway Lipids Location Lower Respiratory Tract Infection Lung Lung infections Mediating Metabolic Metabolic syndrome Metabolism Mitochondria Modeling Mutation Obesity Organ Outcome Pathogenesis Pathway interactions Pattern Peripheral Phase Play Population Primary Infection Production Pulmonary tularemia Recording of previous events Reproducibility Resolution Role Route Structure Surface T cell response T-Lymphocyte Tissues Tularemia Vaccination Vaccines Virulent adaptive immune response adaptive immunity capsule cell type effector T cell in vivo insight lipidomics lung pathogen macrophage metabolomics microbial microorganism mouse model multiple omics novel therapeutics novel vaccines pathogen programs protective efficacy response secondary infection tool vaccination strategy

项目摘要

Pulmonary infections represent 5 of the 30 most common causes of death around the world, with lower respiratory infections resulting on average of 4 million deaths each year and the leading cause of death among children under the age of 5. Despite the significance of infections in the lung we understand little about how inflammation and the development of immunity are regulated in this very dynamic organ. The IPP section utilizes a variety of relevant, highly reproducible models of pulmonary infection to dissect out innate and adaptive immune responses that are intrinsic to the host and those that are intrinsic to the infecting pathogen. Specific Aim 1: Development of long lived immunity against a wide variety of pulmonary pathogens has been difficult to achieve. In some cases, generation of novel vaccines has been impaired by the lack of comprehensive understanding both the elements of the microorganism and the host response that are required to drive adaptive immunity. This is, in part, due to a lack of tools that can aid in delineation of protective versus non-protective (as determined by survival) immune responses. Francisella tularensis (FT) is one such pathogen. By using different models of infection, e.g. B. pertussis, that engender stronger adaptive immunity we are identifying the gaps in current vaccine models for F. tularensis that impair development of long lived immunity. Over the past year we made our major advance in understanding the requirements for strong adaptive immune responses directed against FT were uncovered as a role for effector T cells in the lung. We have determined the relative contribution of resident pulmonary T cells and T cells that circulate through the pulmonary compartment for protection against FT. Specifically, it appears that, while both population of cells is critical for clearance of the virulent bacterium, there is a strong temporal requirement for each population. Thus, vaccination strategies that greatly expand both populations are required for optimal development of new vaccines directed against tularemia. We identified a critical role for the metabolite itaconate in development of adaptive immune responses to F. tularensis. However, the protective role itaconate plays in secondary infection is macrophage intrinsic and not due to direct modulation of T cell responses by the metabolite itself. Together have uncovered an important features of pulmonary T cell immunity that was not previously appreciated and will impact development of new vaccines against an array of pulmonary pathogens. Specific Aim 2: We have identified specific metabolic perturbations in the host that are associated with route of infection Over the past year we have utilized our expertise in immunometabolism and imaging to identify early shifts in host metabolites following infection with FT. Importantly, we have identified that there are specific patterns of production of metabolites that are intrinsic to the route of infection, e.g. intranasal versus intradermal. We have contrasted these responses with a well-defined microbial trigger, LPS. These data provide insight into how the route of infection influences subsequent host metabolic responses. Specific Aim 3: We have established that FT lipids and its capsule direct an anti-inflammatory program in host cells and tissues Over the past year we have further dissected the mechanism by which FT lipid and capsule suppress host cell responses by redirecting host metabolism. We have discovered that these molecules independently manipulate mitochondrial function to establish and anti-inflammatory state in the cell. We have also found that both components contribute to inhibiting specific cell death pathways throughout infection. We have also found that strains of Francisella with targeted mutations in lipid synthesis pathways are attenuated following in vivo infection, thus underscoring the importance of specific lipid classes.

肺部感染代表了全球30个最常见的死亡原因中的5种，下呼吸道感染平均每年导致400万人死亡，以及5岁以下儿童的主要死亡原因。尽管感染在肺中的重要性很少，但我们对这种动态动态有何炎症和免疫发展的调节程度几乎没有理解。 IPP部分利用各种相关的，高度可重现的肺部感染模型来剖析与宿主固有的先天和适应性免疫反应，以及那些对感染病原体固有的植物。特定目的1：对多种肺病原体的长期生命免疫力的发展很难实现。在某些情况下，由于缺乏微生物的元素和驱动适应性免疫所需的宿主反应，新型疫苗的产生受到了损害。这部分是由于缺乏可以帮助描述保护性与非保护性（由生存）免疫反应的工具。弗朗西斯菌（Francisella tularensis）（ft）就是一种病原体。通过使用不同的感染模型，例如B.百日咳，使得更强的适应性免疫力我们正在识别当前疫苗模型的差异，以损害长期生存免疫力的发育。在过去的一年中，我们在理解针对FT的强适应性免疫反应的要求方面取得了重大进步，作为肺中效应T细胞的作用。我们已经确定了通过肺部室循环以保护FT的居民肺T细胞和T细胞的相对贡献。具体而言，看来，尽管两个细胞群对于清除有毒细菌至关重要，但对于每个人群都有很大的时间要求。因此，需要极大地扩展两种种群的疫苗接种策略，才能最佳开发针对Tularemia的新疫苗。我们确定了代谢产物Itaconate在发展对f。tularensis的自适应免疫反应中的关键作用。然而，伊塔酸盐在继发感染中的保护作用是巨噬细胞的内在性，而不是由于代谢产物本身对T细胞反应的直接调节。共同发现了肺T细胞免疫的重要特征，该特征以前尚未得到理解，并将影响新疫苗的发育与一系列肺病病原体。特定目标2：我们已经确定了与感染途径相关的主机中的特定代谢扰动在过去的一年中，我们利用了我们在免疫代谢和成像方面的专业知识来鉴定宿主代谢产物在FT感染后的早期转变。重要的是，我们已经确定存在特定的代谢产物生产模式，这些模式与感染途径固有，例如鼻内与皮内。我们将这些响应与定义明确的微生物触发lps进行了对比。这些数据提供了有关感染途径如何影响随后的宿主代谢反应的洞察力。特定目的3：我们已经确定FT脂质及其胶囊在宿主细胞和组织中指导抗炎程序在过去的一年中，我们进一步阐述了FT脂质和胶囊通过重定向宿主代谢抑制宿主细胞反应的机制。我们已经发现，这些分子独立操纵线粒体功能以在细胞中建立和抗炎状态。我们还发现，这两个成分有助于抑制整个感染过程中特定的细胞死亡途径。我们还发现，在体内感染后，在脂质合成途径中具有靶向突变的弗朗西斯菌菌株会减弱，从而强调了特定脂质类别的重要性。