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.

肺部感染占全球 30 个最常见死亡原因中的 5 个，下呼吸道感染每年平均导致 400 万人死亡，是 5 岁以下儿童死亡的主要原因。尽管肺部感染很重要，但我们对这个非常活跃的器官如何调节炎症和免疫发展知之甚少。 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反应以及感染病原体固有的免疫反应。 具体目标 1：针对多种肺部病原体的长期免疫力的发展一直难以实现。 在某些情况下，由于缺乏对驱动适应性免疫所需的微生物成分和宿主反应的全面了解，新型疫苗的开发受到了损害。部分原因是缺乏可以帮助区分保护性与非保护性（由生存率决定）免疫反应的工具。土拉弗朗西斯菌就是这样的一种病原体。 通过使用不同的感染模型，例如百日咳博德特氏菌，产生更强的适应性免疫，我们正在确定当前土拉热百日咳博德特氏菌疫苗模型中存在的缺陷，这些缺陷会损害长期免疫的发展。 在过去的一年里，我们在了解针对 FT 的强适应性免疫反应的要求方面取得了重大进展，并发现了肺部效应 T 细胞的作用。我们发现初免-加强策略对于激发针对 FT 感染的长期免疫力至关重要。我们已经确定了肺内常驻 T 细胞和通过肺室循环的 T 细胞对预防 FT 的相对贡献。具体来说，虽然这两个细胞群对于清除有毒细菌都至关重要，但每个细胞群都有很强的时间要求。因此，为了优化开发针对兔热病的新疫苗，需要极大地扩大两种人群的疫苗接种策略。我们还发现，肺部的常驻 T 细胞和循环 T 细胞的代谢潜力存在差异，这会影响它们参与抗菌反应的能力。重要的是，这不仅限于针对弗朗西斯氏菌的疫苗接种，还适用于其他不相关细菌的疫苗接种。最后，我们发现土拉弗朗西斯菌会触发特定宿主细胞代谢物的产生，这些代谢物会直接损害 IFN-γ 活性，这与干扰受体介导的反应不同。 这表明我们发现了肺 T 细胞免疫的一个重要特征，这一特征以前未被认识到，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 脂质及其胶囊可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。我们发现这些分子独立地操纵线粒体功能以在细胞中建立抗炎状态。我们还发现，这两种成分都有助于抑制整个感染过程中的特定细胞死亡途径。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会减弱，从而强调了特定脂质类别的重要性。