Franciscella Tularensis: Characterizing Lung Innate Immunity

描述(申请人提供)：图拉氏方济氏菌是图拉热症的病原体，是细胞内的革兰氏阴性球菌。图拉氏丝虫可以在水、潮湿的土壤、干草、稻草和腐烂的动物身体中在低温下存活数周。它的耐寒特性和吸入后的潜在致命影响使这种有机体成为武器化的吸引力。这种细菌是吸入时发现的最具传染性的病原体之一，但人们对图拉氏杆菌如何与其人类宿主相互作用知之甚少。缺乏关于这种高毒力有机体的信息的一个原因是对BSL 3安全程序的要求，这使得相关的研究工作变得密集。关于图拉氏丝虫与常驻肺细胞，特别是肺泡上皮细胞(AEC)和人肺微血管内皮细胞(HPMEC)之间的相互作用，几乎一无所知。呼吸道上皮是外界环境与宿主之间的动态界面。AEC对于维持肺内环境的稳定和提供对吸入病原体的物理屏障至关重要。AEC提供的两种诱导防御机制包括产生抗菌因子和分泌细胞因子以招募和激活免疫细胞。因此，我建议研究肺AEC和HPMEC如何对图拉氏F菌(Schu 4)毒力株做出反应，以促进免疫细胞的迁移和激活。这项建议的第二个目标将是在小鼠鼻腔模型中检测AEC对图拉氏丝虫的反应，并将这些结果与目标1中的人类细胞研究相关联。这些研究将首次为理解图拉氏丝虫和AEC的相互作用以及人肺上皮/内皮细胞和免疫细胞之间的细胞-细胞通讯提供重要信息。这对于深入了解图拉热症的致病性是至关重要的，并将使我们能够确定有针对性的疫苗开发的新途径。 图拉氏丝虫可以被用作对抗公众的生物武器。因此，这项应用提出了更好地了解这种生物如何与肺细胞相互作用以及肺细胞对图拉氏杆菌的反应。这项提议的资金将提供对有效和无效的先天免疫反应的关键洞察，以帮助寻找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.