Francisella tularensis Pathogenesis

摘要/摘要 图拉氏方济氏菌是一种毒性极强的革兰氏阴性细菌，能迅速引起 在包括人类在内的数百种不同的动物物种中不断发展致命感染。传输 从受感染的动物到人类通过多种途径发生，包括直接接触，节肢动物媒介， 进食和吸气。感染剂量最低，疾病进展最快，死亡率最高 与吸入性后天感染有关。图拉氏丝孢杆菌入侵(或进入)并在许多 不同的宿主细胞类型，包括巨噬细胞、树突状细胞、中性粒细胞和至少一些上皮细胞 类型。进入后，细菌逃离吞噬小体，在宿主细胞的细胞质内复制。 我们已经鉴定出一种在致病性弗朗西斯氏菌中保守的细胞质膜蛋白ripA。 物种。缺乏RipA的突变体可以逃脱吞噬小体，但不能在细胞质中复制一次。基因 Dripa突变体的表达模式不同于野生型生物。在这里，我们给出的数据表明 RipA蛋白与转录调节因子ICLR有关，而ICLR调节有限数量的 基因，最著名的是含有反应调节因子pmrA的操纵子，这是图拉氏菌所必需的 细胞内生长和发病机制。提出了三个目标来描述RIPA的特征和辨别其功能 在宿主细胞适应中，确定ICLR在调节相关毒力表达中的作用 并检测3个RipA相关基因对图拉氏丝虫毒力和致病力的影响。 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.