Molecular pathogenesis of Francisella tularnesis

致命疾病图拉热症的病原体，图拉氏方济氏菌(Ft)，是高度革兰氏阴性的 传染性胞内细菌，被归类为A类精选生物恐怖分子。细胞内 巨噬细胞内Ft的复制是疾病表现所必需的。这是相当令人惊讶的 对于这种多功能和致病机制的分子和细胞方面的知识相对匮乏 极其致命的病原体。我们的初步数据表明，当进入巨噬细胞时，含有Ft的 吞噬小体(FCP)逃避溶酶体融合。有机体从吞噬小体逃逸到细胞质中 感染后2-12h。我们的假设是，Ft进入巨噬细胞的特定模式允许 生物体通过特定的出口细菌效应物，调节其吞噬小体的生物发生，形成 不与溶酶体融合，允许有机体随后逃逸到细胞质中，在那里它 复制。为了验证这一假说，我们的具体目标是：1.剖析细胞内F. 在未酸化的晚期类内吞体停止吞噬小体生物发生的独特机制 舞台。鉴定在阻止吞噬小体生物发生和逃逸到细胞质中存在缺陷的突变体。 。确定参与阻止吞噬小体生物生成和逃逸到 细胞质。意义：A类精选生物恐怖分子Ft的发病机制是最少的之一 对细胞内细菌病原体进行研究和了解。了解这种有机体是如何利用 巨噬细胞的增殖和疾病表现是我们了解图拉热症的基础。这个 参与巨噬细胞开发的细菌效应物是潜在的治疗目标 潜在的疫苗候选者。

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.