Immunity to Pulmonary Infections

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，但我们对这个非常动态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。

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.