Tyrosine phosphorylation during A. phagocytophilum invasion

A. phagocytophilum 入侵过程中的酪氨酸磷酸化

• 批准号: 7385148
• 负责人: JACOB W IJDO
• 金额: $ 18.09万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-16 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385148
• 关键词: Anaplasma phagocytophilum; Area; Bacteria; Biology; Cell physiology; Cells; Development; Disease; Ensure; Environment; Generations; Goals; Human; Immune system; Incidence; Infection; Inflammation; Life Style; Lyme Disease; Mediating; Modeling; NADP; NADPH Oxidase; Organism; PTPN6 gene; Pathway interactions; Phagocytes; Play; Protein Binding; Proteins; Reactive Oxygen Species; Respiratory Burst; Role; SH3 Domains; Signal Pathway; Ticks; Type IV Secretion System Pathway; Tyrosine; Tyrosine Phosphorylation; United States; factor A; human granulocytic ehrlichiosis; in vivo; killings; neutrophil; pathogen; src Homology Region 2 Domain

Description: Intracellular organisms manipulate their host cells to suit their intracellular life styles. These pathogens alter cellular processes by introducing bacterial factors into the host cell. Anaplasma phagocytophilum, which causes Human Granulocytic Ehrlichiosis, is a unique intracellular organism because it is the only human pathogen that specifically survives and multiplies in neutrophils. Neutrophils play an essential role in the immune system and kill bacteria very efficiently. A. phagocytophilum is the exception as it escapes killing by neutrophils. It is poorly understood how A. phagocytophilum manipulates the cellular processes in the neutrophil for its survival. The global hypothesis is that A. phagocytophilum manipulates cellular processes by translocating bacterial factors into the neutrophil ensuring its survival. We have identified a candidate bacterial factor, AnkA, which may mediate these effects. Consequently, A. phagocytophilum infection of neutrophils provides an ideal model to study the pathways involved in neutrophil biology and bacterial killing. Aim 1 examines the tyrosine phosphorylation of AnkA, which allows it to interact with specific host cells proteins through SH2 domains. Aim 2 seeks to identify these host cell proteins and the signaling pathways manipulated by AnkA. Aim 3 examines the effect of AnkA on the respiratory burst, the major killing pathway of the neutrophil. The long-term goals are: 1) the identification of the mechanism leading to survival of A. phagocytophilum in neutrophils, 2) the development new avenues to manipulate neutrophils, leading to potential new treatments of inflammation or infections, and 3) enhancement of our understanding of neutrophil biology as it relates to the immune system. In the Unites States, Human Granulocytic Ehrlichiosis is an emerging tick-associated disease and in endemic areas the incidence is second only to Lyme disease.

描述：细胞内生物操纵其宿主细胞以适应其细胞内生活方式。这些病原体通过将细菌因子引入宿主细胞来改变细胞过程。嗜吞噬细胞无形体， 引起人类粒细胞埃利希体病，是一种独特的细胞内生物，因为它是人类唯一的 特异性在中性粒细胞中生存和繁殖的病原体。中性粒细胞在 免疫系统并非常有效地杀死细菌。 A. phagocytophilum 是个例外，因为它逃脱了杀戮 由中性粒细胞。目前人们对 A. phagocytophilum 如何操纵细胞过程知之甚少。 中性粒细胞的生存。 普遍的假设是，嗜吞噬细胞放线菌通过将细菌因子转移到中性粒细胞中来操纵细胞过程，确保其存活。我们已经确定了一种候选细菌因子 AnkA，它可以介导这些效应。因此，嗜中性粒细胞的 A. phagocytophilum 感染提供了理想的 模型来研究中性粒细胞生物学和细菌杀灭所涉及的途径。 目标 1 检查 AnkA 的酪氨酸磷酸化，使其能够与特定宿主细胞相互作用 通过 SH2 结构域的蛋白质。 目标 2 旨在鉴定这些宿主细胞蛋白以及 AnkA 操纵的信号通路。 目标 3 检查 AnkA 对呼吸爆发（中性粒细胞的主要杀伤途径）的影响。 长期目标是： 1) 鉴定导致 A. phagocytophilum 存活的机制 中性粒细胞，2）开发操纵中性粒细胞的新途径，导致潜在的新途径 炎症或感染的治疗，3) 增强我们对中性粒细胞生物学的理解 它与免疫系统有关。 在美国，人类粒细胞埃利希体病是一种新出现的蜱相关疾病，在 流行地区发病率仅次于莱姆病。