Molecular pathogenesis of Francisella tularnesis

致命性疾病土拉热病的病原体，土拉热弗朗西斯菌（Ft），是一种革兰氏阴性高度 感染性细胞内细菌，被归类为A类选择生物恐怖主义制剂。细胞内 巨噬细胞内Ft的复制对于疾病表现是必需的。令人惊讶的是， 相对缺乏知识的分子和细胞方面的发病机制，这种多功能和 极其致命的病原体我们的初步数据表明，在进入巨噬细胞，含FT 吞噬体（FCP）逃避溶酶体融合。生物体从吞噬体逃逸到细胞质中 感染后2- 12小时。我们的假设是，Ft进入巨噬细胞的特定模式允许Ft进入巨噬细胞。 生物体通过特定的输出细菌效应物调节其吞噬体的生物发生，进入一个生态位， 不融合到溶酶体，并允许随后的生物体逃逸到细胞质中， 复制品。为了验证这一假设，我们的具体目标是：对胞内F. 土拉热和独特的机制，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。 .为了表征参与阻止吞噬体生物合成和逃逸到 细胞质意义：A类生物恐怖剂Ft的发病机制是最小的一种 在细胞内细菌病原体中研究和理解。了解这种生物如何利用 巨噬细胞的增殖和疾病表现是我们了解兔热病的基础。的 参与利用巨噬细胞的细菌效应物是治疗的潜在靶点， 潜在的疫苗候选人

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. . 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.