Immunity to Pulmonary Infections

对肺部感染的免疫力

• 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
• 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

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.

肺部感染占全世界30个最常见死亡原因中的5个，下呼吸道感染平均每年造成400万人死亡，是5岁以下儿童死亡的主要原因。尽管肺部感染的重要性，但我们对这个非常活跃的器官如何调节炎症和免疫的发展知之甚少。IPP部分利用各种相关的、高度可重复的肺部感染模型来解剖宿主固有的和感染病原体固有的先天和适应性免疫反应。