Immunity to Pneumonic Tularemia

图拉氏方济各氏菌(FT)是图拉热病的病原体，可通过多种途径感染人类，包括媒介传播。然而，吸入细菌以及由此导致的肺炎图拉热症是最危险的疾病形式。这是由于未经治疗的患者的潜伏期短(3-5天)、非特异性症状以及高死亡率(大于80%)。此外，英国《金融时报》已经被美国和前苏联武器化，使其成为一个可行的生物武器候选者。尽管世界各地对FT的研究已有80多年的历史，但人们对这种细菌与宿主的动态相互作用知之甚少，尤其是在气溶胶感染之后。 具体目标1：目前没有获得许可的图拉热症疫苗。由于缺乏对驱动FT适应性免疫所需的细菌成分和宿主反应的全面了解，新疫苗的开发受到了阻碍。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。 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。我们发现，优质增强策略对于激发对FT感染的长期免疫力至关重要。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口的疫苗接种策略。 具体目标2和3：我们已经建立了FT脂质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。

Francisella tularensis (FT), the causative agent for tularemia, can infect humans by a number of routes, including vector-borne transmission. However, inhalation of the bacterium, and the resulting pneumonic tularemia, is the most dangerous form of disease. This is due to the short incubation time (3-5 days), non-specific symptoms, and a high mortality rate (greater than 80%) in untreated individuals. Furthermore, FT has been weaponized by both the United States and the former Soviet Union making it a viable candidate for use as a biological weapon. Despite over 80 years of research on FT around the world, very little is understood about the dynamic interaction of this bacterium with the host, especially following aerosol infection. Specific Aim 1: There are no vaccines currently licensed for tularemia. Development of novel vaccines has been impaired by the lack of comprehensive understanding both the elements of the bacterium and the host response that are required to drive adaptive immunity against FT. 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. 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. 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.