Molecular pathogenesis of Francisella Tularensis

描述（由申请方提供）：致死性疾病土拉菌病的病原体，土拉热弗朗西斯菌（Ft），是一种革兰氏阴性高感染性细胞内细菌，被归类为A类选择生物恐怖主义病原体。巨噬细胞内Ft的细胞内复制是疾病表现所必需的。这是相当惊人的知识相对缺乏分子和细胞方面的发病机制，这种多功能和极端致命的病原体。我们的初步数据表明，进入巨噬细胞后，含FT的吞噬体（FCP）逃避溶酶体融合。感染后2- 12小时，生物体从吞噬体逃逸到细胞质中。我们的假设是，特定的模式进入巨噬细胞的Ft允许生物体调节其吞噬体的生物合成，通过特定的出口细菌效应子，进入一个小生境，不融合到溶酶体，并允许随后逃逸的生物体进入细胞质，在那里它复制。为了验证这一假设，我们的具体目标是：对胞内F. tularensis和独特的机制，停止吞噬体生物发生在非酸化晚期内体样阶段。二.鉴定在阻止吞噬体生物合成和逃逸到细胞质中有缺陷的突变体。三.表征参与阻止吞噬体生物合成并逃逸到细胞质中的细菌因子。重要性：A类生物恐怖主义病原体的发病机制Ft是细胞内细菌病原体中研究和了解最少的病原体之一。了解这种微生物如何利用巨噬细胞进行增殖和疾病表现是我们了解兔热病的基础。参与利用巨噬细胞的细菌效应物是潜在的治疗靶点以及潜在的疫苗候选物。

DESCRIPTION (provided by applicant): The causative agent of the fatal disease Tularemia, Francisella tularensis (Ft), is a gram negative highly infectious intracellular bacterium, that is classified as a Category A Select Bioterrorism Agent. Intracellular replication of Ft within macrophages is essential for disease manifestation. It is rather astonishing the relative paucity of knowledge about the molecular and cellular aspects of pathogenesis of this versatile and extremely virulent pathogen. Our preliminary data indicate that upon entry into macrophages, Ft-containing phagosome (FCP) evades lysosomal fusion. The organism escapes from the phagosome into the cytoplasm by 2-12h post-infection. Our hypothesis is that specific modes of entry of Ft into macrophages allow the organism to modulate biogenesis of its phagosome, by specific exported bacterial effectors, into a niche that does not fuse to the lysosomes and allow subsequent escape of the organism into the cytoplasm, where it replicates. To test this hypothesis, our specific aims are: I. To dissect the cell biology of intracellular F. tularensis and the unique mechanisms that halt phagosome biogenesis at a non-acidified late endosome-like stage. II. To identify mutants defective in arresting phagosome biogenesis and escape into the cytoplasm. III. To characterize the bacterial factors involved in arresting phagosome biogensis and escape into the cytoplasm. Significance: Pathogenesis of the Category A Select Bioterrorism Agent Ft is one of the least studied and understood among intracellular bacterial pathogens. Understanding how this organism exploits macrophages for proliferation and disease manifestation is fundamental to our knowledge of tularemia. The bacterial effectors involved in exploiting the macrophage are potential targets for treatment as well as potential vaccine candidates.