Franciscella Tularensis: Characterizing Lung Innate Immunity

描述（由申请方提供）：土拉热弗朗西斯菌是土拉菌病的病原体，是细胞内革兰氏阴性球菌。F.土拉热菌可以在水、潮湿的土壤、干草、稻草和腐烂的动物尸体中在低温下存活数周。它的哈代特性和吸入后的潜在致命影响使这种生物体成为武器的吸引力。这种细菌是最具传染性的病原体之一，当吸入时，但很少有人知道F。土拉热菌与其人类宿主相互作用。缺乏关于这种高毒性微生物的信息的一个原因是BSL 3安全程序的要求，这使得相关的研究劳动密集型。事实上，对F之间的相互作用一无所知。土拉热菌和驻留肺细胞，特别是肺泡上皮细胞（AEC）和人肺微血管内皮细胞（HPMEC）。呼吸道上皮是外界环境与宿主之间的动态界面。AEC对于维持肺内环境稳定和提供对吸入病原体的物理屏障至关重要。AEC提供的两种诱导性防御机制包括产生抗微生物因子和分泌细胞因子以募集和激活免疫细胞。因此，我建议研究肺AEC和HPMEC对F.土拉热菌（Schu 4）促进免疫细胞迁移和活化。本提案的第二个目标是检查原子能委员会对F.在鼻内小鼠模型中研究土拉热，并将这些结果与Aim 1中的人细胞研究相关联。这些研究将首次为理解F. tularensis和AEC之间的细胞间通讯以及人肺上皮/内皮和免疫细胞对F.土拉热。这对于深入了解兔热病的致病性至关重要，并将使我们能够确定靶向疫苗开发的新途径。 F.土拉热可以被用作针对公众的生物武器。因此，本申请提出更好地理解该生物体如何与肺细胞相互作用以及肺细胞对F.土拉热。该提案的资助将为有效和无效的先天免疫反应提供关键的见解，以帮助找到未来的疫苗和治疗开发。

DESCRIPTION (provided by applicant): Francisella tularensis, the etiological agent of tularemia, is intracellular Gram-negative cocci. F. tularensis can survive for weeks at low temperatures in water, moist soil, hay, straw, and decaying animal carcasses. Its hardy nature and potentially lethal effects following inhalation have made this organism attractive for weaponization. This bacterium is one of the most infectious pathogens identified when inhaled, and yet very little is known about how F. tularensis interacts with its human host. One reason for the lack of information about this highly virulent organism is the requirement for BSL 3 safety procedures that makes associated research labor intensive. Virtually nothing is known about the interaction between F. tularensis and resident lung cells, specifically alveolar epithelial cells (AEC) and human pulmonary microvascular endothelial cells (HPMEC). The respiratory epithelium is a dynamic interface between the outside environment and the host. AEC are vital for maintaining lung homeostasis and providing a physical barrier against inhaled pathogens. Two inducible defense mechanisms provided by AEC include the production of antimicrobial factors and secreting cytokines for the recruitment and activation of immune cells. Therefore, I propose to examine how pulmonary AEC and HPMEC respond to a virulent strain of F. tularensis (Schu 4) to promote immune cell migration and activation. The second goal of this proposal will be to examine the response of AEC to F. tularensis in an intranasal mouse model and correlate these results with the human cell studies in Aim 1. These studies will, for the first time, provide vital information for understanding the interaction of F. tularensis and AEC and the cell-cell communication between human lung epithelium/endothelium and immune cells in response to F. tularensis. This is essential for gaining insight into the pathogenicity of tularemia, and will allow us to identify novel avenues for targeted vaccine development. F. tularensis can be used as a bioweapon against the public. Therefore, this application proposes to better understand how this organism interacts with lung cells and responses of the lung cells to F. tularensis. This funding of this proposal will provide crucial insight into the effective and ineffective innate immune responses to help find future vaccines and therapeutic development.