Immunity to Pulmonary Infections

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。尽管肺部感染的重要性，我们对这个非常动态的器官中炎症和免疫力的发展是如何调节的知之甚少。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，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，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（由存活率确定）免疫应答的工具。土拉热弗朗西丝氏菌（FT）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。我们确定了代谢产物衣康酸在对F.土拉热。然而，衣康酸在继发性感染中的保护作用是巨噬细胞内在的，而不是由于代谢产物本身直接调节T细胞反应。他们共同揭示了肺部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：我们已经确定了宿主中与感染途径相关的特定代谢紊乱 在过去的一年中，我们利用我们在免疫代谢和成像方面的专业知识来确定感染FT后宿主代谢物的早期变化。 重要的是，我们已经确定存在感染途径固有的代谢物产生的特定模式，例如鼻内与皮内。 我们将这些反应与定义明确的微生物触发剂LPS进行了对比。 这些数据提供了深入了解感染途径如何影响随后的宿主代谢反应。 具体目标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。

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.