Immunity to Pulmonary Infections

肺部感染是世界上最常见的30种死亡原因中的5种，其中下呼吸道感染每年平均导致400万人死亡，是5岁以下儿童的主要死亡原因。尽管肺部感染具有重要意义，但我们对炎症和免疫发展如何在这个非常活跃的器官中进行调节知之甚少。IPP部分利用各种相关的、高度可重复性的肺部感染模型来剖析宿主固有的先天和获得性免疫反应以及感染病原体固有的免疫反应。 具体目标1：发展对各种肺部病原体的长期免疫一直很难实现。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了解，新疫苗的产生受到了影响。这在一定程度上是由于缺乏能够帮助区分保护性和非保护性(由存活率决定)免疫反应的工具。图拉氏方济氏菌(Francisella tularensis，FT)就是这样一种病原菌。通过使用不同的感染模式，例如百日咳杆菌，产生更强的获得性免疫，我们正在识别当前图拉丝虫疫苗模型中损害长期免疫发展的空白。 在过去的一年里，我们在理解针对FT的强烈适应性免疫反应的要求方面取得了重大进展，发现肺中效应性T细胞的作用。我们已经确定了常驻肺T细胞和通过肺间隔循环的T细胞对FT的保护作用的相对贡献。具体地说，尽管这两个群体的细胞对清除毒力细菌至关重要，但每个群体都有很强的时间需求。因此，为了最佳地开发针对图拉热症的新疫苗，需要极大地扩大这两个人群的疫苗接种策略。我们确定了代谢产物衣康酸在发展对图拉氏丝虫的适应性免疫反应中的关键作用。然而，衣康酸在继发感染中的保护作用是巨噬细胞固有的，而不是由于代谢物本身对T细胞反应的直接调节。共同揭示了肺T细胞免疫的一个以前没有被认识到的重要特征，并将影响针对一系列肺部病原体的新疫苗的开发。 特定目标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 在过去的一年里，我们利用我们在免疫代谢和成像方面的专业知识来识别感染FT后宿主代谢物的早期变化。重要的是，我们已经确定了感染途径所固有的代谢物产生的特定模式，例如鼻内和皮内。我们将这些反应与一种定义明确的微生物触发物--内毒素--进行了对比。这些数据提供了对感染途径如何影响随后的宿主代谢反应的洞察。 具体目标3：我们已经建立了FT脂类及其胶囊在宿主细胞和组织中指导抗炎程序 在过去的一年里，我们进一步剖析了FT脂质和胶囊通过改变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的功能，以建立和抗炎状态的细胞。我们还发现，在整个感染过程中，这两种成分都有助于抑制特定的细胞死亡途径。我们还发现，在体内感染后，脂类合成途径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.