Human pathogenic bacterium induces actin phosphorylation to selectively regulate

人类致病菌诱导肌动蛋白磷酸化选择性调节

• 批准号: 8260845
• 负责人: Hameeda Sultana
• 金额: $ 3.52万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260845
• 关键词: 1-Phosphatidylinositol 3-Kinase; Actins; Address; Affinity; Anaplasma phagocytophilum; Arthropod Vectors; Arthropods; Bacteria; Binding; Binding Proteins; Biological Assay; Black-legged Tick; Bovine Anaplasmosis; Cell Nucleus; Cells; Cytoskeleton; DNA; Data; Electrophoretic Mobility Shift Assay; F-Actin; G Actin; G-Protein-Coupled Receptors; Gene Expression Regulation; Genes; Genetic Transcription; Human; Infection; Ixodes; Life Cycle Stages; Mammals; Mediating; Mediator of activation protein; Medical; Microbe; Modeling; Molecular; Myosin ATPase; Myosin Light Chains; Nuclear; PIK3CG gene; Phosphorylation; Precipitation; Proteins; RNA Polymerase II; Regulation; Rickettsia; Role; Signal Transduction; Specificity; TATA Box; Ticks; Time; Transcription Coactivator; United States; Vector-transmitted infectious disease; neglect; novel; pathogen; pathogenic bacteria; promoter; public health relevance; vector

DESCRIPTION (provided by applicant): Many bacterial pathogens exploit host actin cytoskeleton either during entry/internalization or spread from cell to cell. Pathogen use of the actin cytoskeleton in arthropod vectors has not yet been explored. Using Ixodes scapularis ticks and Anaplasma phagocytophilum (the agent of human granulocytic anaplasmosis) as an infection model, I provide evidence for the first time to show how an obligate intracellular bacterium can exploit the actin cytoskeleton to control arthropod gene transcription for its own benefit. My preliminary results show that A. phagocytophilum induces the phosphorylation of tick actin and subsequently alters the ratio of monomeric/filamentous (G/F)-actin. I also show that A. phagocytophilum-induced actin phosphorylation is dependent on Ixodes PAK1-PI3kinase signaling. A. phagocytophilum-induced actin phosphorylation resulted in increased nuclear G-actin and phosphorylated actin that associated with RNA Polymerase II (RNAPII). Induced actin phosphorylation in the nucleus enhanced binding of TATA-box-binding-protein to RNAPII and caused the selective regulation of salp16, a gene crucial for A. phagocytophilum survival. This project proposal explores to identify the mechanism by which selective regulation of salp16 promoter is mediated upon A. phagocytophilum infection. Additional studies are proposed to identify whether any of the bacterial component(s) or other Ixodes transcriptional activator(s) are involved in this specific gene regulation. Collectively, this study may provide evidence for a novel role of actin phosphorylation during host- pathogen interaction and suggest new strategies to interfere with the life cycle of this obligate intracellular pathogen, and perhaps other Rickettsia-related microbes of medical importance. PUBLIC HEALTH RELEVANCE: In United States, Ixodes scapularis ticks transmit several human pathogens including A. phagocytophilum, the agent of human anaplasmosis. The molecular mechanisms that this bacterium uses to survive in its vector host are currently not understood. This project proposal provides evidence for a novel role of actin during host-pathogen interaction and suggests new strategies to interfere with the life cycle of this obligate intracellular pathogen, and perhaps other arthropod-borne microbes of medical importance.

描述（由申请人提供）：许多细菌病原体在进入/内部化过程中剥削宿主肌动蛋白细胞骨架，或者从细胞到细胞扩散。尚未探讨肌动蛋白细胞骨架的病原体使用。使用ixodes肩tick虫和吞噬吞噬吞噬（人类粒细胞性异性症的药物）作为感染模型，我首次提供了证据，以表明细胞内细菌如何利用肌动蛋白细胞骨骼以控制Arthropod Gene Gene Gene Transcrients自身的益处。我的初步结果表明，肠曲霉诱导tick肌动蛋白的磷酸化，然后改变单体/丝状（G/F） - 肌动蛋白的比率。我还表明，烟曲霉诱导的肌动蛋白磷酸化取决于ixodes Pak1-Pi3kinase信号传导。 A.吞噬细胞诱导的肌动蛋白磷酸化导致与RNA聚合酶II（RNAPII）相关的核G-肌动蛋白和磷酸化肌动蛋白增加。核中诱导的肌动蛋白磷酸化增强了TATA-box结合 - 结合蛋白与RNAPII的结合，并导致Salp16的选择性调节，Salp16的选择性调节，这是吞噬细胞杆菌存活至关重要的基因。该项目提案探讨了以确定在吞噬细胞嗜酸杆菌感染时介导的SALP16启动子选择性调节的机制。提出了其他研究以确定任何细菌成分或其他IXODES转录激活剂是否参与了该特定基因调节。总的来说，这项研究可以提供证据证明肌动蛋白磷酸化在宿主病原体相互作用过程中的新作用，并提出了新的策略，以干扰这种强制性细胞内病原体的生命周期，以及其他具有医学重要性的立克相关的微生物。 公共卫生相关性：在美国，ixodes capularis tick传递了几种人类病原体，包括人类肿瘤的药物，包括吞噬细胞杆菌。目前尚不清楚该细菌用来在其载体中生存的分子机制。该项目提案为肌动蛋白在宿主 - 病原体相互作用中的新作用提供了证据，并提出了干扰这种细胞内病原体的生命周期的新策略，也许还有其他具有医学重要性的节肢动物传播的微生物。