Francisella tularensis Pathogenesis

总结/摘要 土拉热弗朗西丝氏菌是一种极强的革兰氏阴性细菌病原体，能够迅速引起 在包括人类在内的数百种不同动物物种中进行致命感染。传输 从受感染的动物到人类的传播途径有多种，包括直接接触，节肢动物媒介， 摄入和吸入。最低的感染剂量、最快的疾病进展和最高的死亡率是 与吸入获得性感染有关。F.土拉热侵入（或进入）并在许多 不同的宿主细胞类型，包括巨噬细胞、树突细胞、嗜中性粒细胞和至少一些上皮细胞 类型进入后，细菌逃离吞噬体并在宿主细胞的细胞质内复制。 我们已经确定了一个细胞质膜蛋白，RipA，这是保守的致病弗朗西斯， 物种缺乏RipA的突变体逃脱吞噬体，但在细胞质中复制失败。基因 DripA突变体的表达模式不同于野生型生物。在此，我们提出的数据表明， RipA蛋白与转录调节因子IclR相关，IclR调节有限数量的转录因子。 基因，最值得注意的是一个操纵子含有一个反应调节剂，pmrA，这是所需的F。tularensis 细胞内生长和发病机制。提出了三个目标来表征RipA并识别其功能 在宿主细胞适应中，确定IclR在调节毒力相关基因表达中的作用， 基因，并研究三个RipA相关基因对F.土拉菌毒力和 发病机制

SUMMARY/ABSTRACT Francisella tularensis is an extremely virulent Gram negative bacterial pathogen capable of causing rapidly progressing lethal infections in literally hundreds of diverse animal species, including humans. Transmission from infected animals to humans occurs via multiple routes including direct contact, arthropod vectors, ingestion and inhalation. The lowest infective dose, fastest disease progression, and highest mortality rates are associated with inhalation acquired infections. F. tularensis invades (or enters) and replicates within many different host cell types, including macrophages, dendritic cells, neutrophils and at least some epithelial cell types. Following entry the bacteria escape the phagosome and replicate within the cytoplasm of the host cell. We have identified a cytoplasmic membrane protein, RipA, that is conserved among pathogenic Francisella species. Mutants lacking RipA escape the phagosome, but fail to replicate once in the cytoplasm. Gene expression patterns in DripA mutants differ from wild type organisms. Herein we present data demonstrating that the RipA protein associates with a transcriptional regulator, IclR, and IclR regulates a restricted number of genes, most notably an operon containing a response regulator, pmrA, that is required for F. tularensis intracellular growth and pathogenesis. Three aims are proposed to characterize RipA and discern its function in host cell adaptation, to determine the role of IclR in modulating the expression of virulence associated genes, and to examine the contribution of three RipA - associated genes to F. tularensis virulence and pathogenesis.