Francisella tularensis Pathogenesis

土拉弗朗西斯菌发病机制

• 批准号: 8080561
• 负责人: Thomas H KAWULA
• 金额: $ 3.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-14 至 2010-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080561
• 关键词: Affect; Alleles; Amino Acid Sequence Homology; Animals; Arthropod Vectors; Bacteria; Biochemical; Biological; Biology; Bite; Breathing; Cell membrane; Cells; Containment; Cytoplasm; Data; Databases; Dendritic Cells; Disease Progression; Dose; Environment; Epithelial Cells; Francisella; Francisella tularensis; Frequencies; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Gram-Negative Bacterial Infections; Growth; Helix-Turn-Helix Motifs; Human; Immune response; Immunosuppression; Infection; Ingestion; Invaded; Laboratories; Learning; Lung diseases; Mediating; Membrane Proteins; Methods; Microarray Analysis; Modeling; Mutagenesis; Mutation; Operon; Organism; Orphan; Pathogenesis; Pattern; Phagosomes; Phenotype; Property; Proteins; Research; Role; Route; Time; Virulence; Virulent; Winged Helix; abstracting; base; cell type; improved; in vivo; insertion/deletion mutation; macrophage; mortality; mutant; neutrophil; numb protein; pathogen; resilience; response; tool; transmission process

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.

摘要/摘要 土拉弗朗西斯菌是一种毒性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。传播 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。感染剂量最低、疾病进展最快、死亡率最高的是 与吸入性感染有关。 F. tularensis 侵入（或进入）并在许多体内复制 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，细菌逃离吞噬体并在宿主细胞的细胞质内复制。 我们已经鉴定出一种细胞质膜蛋白 RipA，它在致病性弗朗西斯菌中是保守的 物种。缺乏 RipA 的突变体逃脱了吞噬体，但一旦进入细胞质就无法复制。基因 DripA 突变体的表达模式与野生型生物体不同。在此我们提供数据证明 RipA 蛋白与转录调节因子 IclR 相关，并且 IclR 调节有限数量的 基因，最显着的是含有反应调节因子 pmrA 的操纵子，这是土拉弗拉菌所必需的 细胞内生长和发病机制。提出了三个目标来表征 RipA 并辨别其功能 在宿主细胞适应中，确定 IclR 在调节相关毒力表达中的作用 基因，并检查三个 RipA 相关基因对 F. tularensis 毒力的贡献 发病。