Immunity to Pulmonary Infections

对肺部感染的免疫力

• 批准号: 10272123
• 负责人: Catharine Bosio
• 金额: $ 153.3万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 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/10272123
• 关键词: Age; Anti-Inflammatory Agents; Attenuated; Attenuated Vaccines; Bacteria; Bordetella pertussis; Cause of Death; Cell Death; Cells; Cessation of life; Child; Development; Dose; Elements; Francisella; Francisella tularensis; Genomics; Goals; Imaging technology; Immune response; Immunity; Immunosuppression; Impairment; Individual; Infection; Infection prevention; Infectious Agent; Inflammation; Inflammatory Response; Interferon Type II; Klebsiella pneumoniae; Lead; Lipid Synthesis Pathway; Lipids; Location; Lower Respiratory Tract Infection; Lung; Lung infections; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Mutation; Organ; Pathogenesis; Pathway interactions; Peripheral; Phase; Play; Population; Primary Infection; Production; Pulmonary tularemia; Recording of previous events; Reproducibility; Resolution; Role; Structure; Surface; T-Lymphocyte; Tissues; Tularemia; Vaccination; Vaccines; Virulent; adaptive immune response; adaptive immunity; antimicrobial; capsule; cell type; effector T cell; in vivo; metabolomics; microorganism; mouse model; multiple omics; novel therapeutics; novel vaccines; pathogen; programs; protective efficacy; receptor; response; secondary infection; tool; vaccination strategy

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 lung infections 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, development 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 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 discovered that a prime- boost strategy is essential for provoking long term immunity against FT infection. 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 population are required for optimal development of new vaccines directed against tularemia. We have also found that resident and circulating T cells in the lung have differences in their metabolic potential that influences their ability to participate in antimicrobial responses. Importantly this was not restricted to vaccination against Francisella but was applicable to vaccination with other unrelated bacterium. Finally, we have shown that F. tularensis triggers production of specific host cell metabolites that directly impair IFN-gamma activity that is distinct from interference with receptor mediated responses. This suggests that we 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 and 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.

肺部感染是全世界30种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，是5岁以下儿童的主要死亡原因。 尽管肺部感染很重要，但我们对这个非常动态的器官中炎症和免疫力发展如何调节知之甚少。 IPP部分利用各种相关的、高度可重复的肺部感染模型来剖析宿主固有的先天性和适应性免疫应答以及感染病原体固有的免疫应答。 具体目标1：开发针对多种肺部病原体的长期免疫力一直难以实现。 在某些情况下，新型疫苗的开发由于缺乏对驱动适应性免疫所需的微生物要素和宿主反应的全面理解而受到损害。这部分是由于缺乏可以帮助描述保护性与非保护性（如由存活率确定的）免疫应答的工具。土拉热弗朗西丝氏菌就是这样一种病原体。 通过使用不同的感染模型，例如B。百日咳，产生更强的适应性免疫，我们正在确定目前的疫苗模型的差距，为F。土拉菌病损害长期免疫力发展。 在过去的一年里，我们在理解针对FT的强适应性免疫应答的要求方面取得了重大进展，发现了效应T细胞在肺中的作用。我们发现，初免-加强免疫策略对于激发针对FT感染的长期免疫是必不可少的。我们已经确定了常驻肺T细胞和通过肺室循环的T细胞对FT的保护的相对贡献。具体而言，似乎虽然两个细胞群体对于清除毒性细菌都是至关重要的，但每个群体都有很强的时间要求。因此，疫苗接种策略，大大扩大两个人口需要针对兔热病的新疫苗的最佳发展。我们还发现，肺中的常驻和循环T细胞在其代谢潜力方面存在差异，这影响了它们参与抗菌反应的能力。重要的是，这并不限于接种抗弗朗西斯菌，但适用于接种其他不相关的细菌。最后，我们证明了F.土拉热引发特异性宿主细胞代谢物的产生，所述代谢物直接损害IFN-γ活性，这与干扰受体介导的应答不同。 这表明我们已经发现了肺部T细胞免疫的一个重要特征，这是以前没有认识到的，并将影响针对一系列肺部病原体的新疫苗的开发。 具体目标2和3：我们已经确定FT脂质及其胶囊指导宿主细胞和组织中的抗炎程序 在过去的一年里，我们进一步剖析了FT脂质和胶囊通过重定向宿主代谢来抑制宿主细胞反应的机制。我们已经发现，这些分子独立地操纵线粒体功能以在细胞中建立和抗炎状态。我们还发现，这两种成分有助于在整个感染过程中抑制特定的细胞死亡途径。我们还发现，在脂质合成途径中具有靶向突变的弗朗西斯菌菌株在体内感染后被减毒，从而强调了特定脂质类的重要性。