Subverted host cell signaling by AnkA in Anaplasma phagocytophilum infection

AnkA 在嗜吞噬细胞无形体感染中破坏宿主细胞信号传导

• 批准号: 7888309
• 负责人: JACOB W IJDO
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7888309
• 关键词: Anaplasma phagocytophilum; Ankyrins; Apoptosis; Bacteria; Binding; Binding Proteins; Biology; Cell physiology; Cells; Collaborations; Cytoplasm; Development; Disease; Environment; Generations; Goals; Human; Immune system; Infection; Inflammation; Laboratories; Lead; Life; Life Style; Lyme Disease; Mediating; Modeling; NADPH Oxidase; Organism; PTPN6 gene; Pathway interactions; Phosphotyrosine; Play; Positioning Attribute; Production; Protein Binding; Proteins; Reactive Oxygen Species; Respiratory Burst; Role; SH3 Domains; Signal Pathway; Signal Transduction; Signaling Protein; Superoxides; System; Ticks; Tyrosine; Tyrosine Phosphorylation; United States; Virulence Factors; human granulocytic ehrlichiosis; killings; neutrophil; neutrophil cytosol factor 67K; pathogen; public health relevance; src Homology Region 2 Domain

DESCRIPTION (provided by applicant): Anaplasma phagocytophilum, is a human pathogen that infects neutrophils and causes Human Granulocytic Ehrlichiosis. In the Unites States it is the second most common tick-associated infection, only surpassed by Lyme disease. Although neutrophils are very efficient in killing bacteria, A. phagocytophilum is the exception as it not only escapes killing by neutrophils, it lives and replicates inside neutrophils. A. phagocytophilum interferes with superoxide-mediated killing and delays neutrophil apoptosis. It is poorly understood how A. phagocytophilum accomplishes these major feats. This proposal seeks to identify the basic mechanism how A. phagocytophilum manipulates these cellular processes. Our recent identification of the first bacterial virulence factor in A. phagocytophilum, AnkA, may play a pivotal role in manipulating neutrophil functions. Consequently, A. phagocytophilum infection of neutrophils provides an ideal model to study the pathways involved in neutrophil biology and bacterial killing. The global hypothesis is that translocated AnkA interferes with host signaling pathways in the neutrophil, resulting in the inhibition of superoxide generation and the delay of apoptosis. Upon bacterial binding to the host cell, AnkA is translocated into the host cell cytoplasm and is then rapidly tyrosine phosphorylated (within seconds to minutes). Tyrosine phosphorylation allows AnkA to bind to SH2 domains of key signaling proteins in the host cell. Further, AnkA may also bind proteins via SH3 domains and ankyrin repeats. Through these putative protein interactions AnkA may alter host cell signaling and cause the cellular changes in neutrophils. Aim 1 seeks to identify the specific interactions of host cell proteins that bind to AnkA Aim 2 proposes to study the role of AnkA in inhibition of killing by the neutrophil. Aim 3 will examine the role of AnkA in the delay of neutrophil apoptosis. 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. PUBLIC HEALTH RELEVANCE: Human Granulocytic Ehrlichiosis, caused by A. phagocytophilum, is the second most common tick- associated disease in the United States. This proposal seeks to investigate how A. phagocytophilum can survive in neutrophils. This may lead to a better understanding of the function of neutrophils within the immune system and may lead to potential new treatments of inflammation and infections.

描述（由申请方提供）：嗜吞噬细胞无形体是一种感染中性粒细胞并引起人粒细胞埃里希体病的人类病原体。在美国，它是第二种最常见的蜱相关感染，仅次于莱姆病。虽然中性粒细胞在杀死细菌方面非常有效，但A.嗜吞噬细胞菌是个例外，因为它不仅能逃脱嗜中性粒细胞的杀伤，而且能在嗜中性粒细胞内生存和复制。A.嗜吞噬细胞菌干扰超氧化物介导的杀伤并延迟中性粒细胞凋亡。人们对A.嗜吞噬细胞菌完成了这些主要的壮举。本研究旨在确定A.嗜吞噬细胞菌操纵这些细胞过程。我们最近在A.嗜吞噬细胞菌AnkA可能在操纵中性粒细胞功能中发挥关键作用。因此，A.嗜吞噬细胞菌感染中性粒细胞为研究中性粒细胞生物学和细菌杀伤途径提供了理想的模型。总体假设是易位的AnkA干扰了中性粒细胞中的宿主信号传导途径，导致超氧化物生成的抑制和细胞凋亡的延迟。当细菌与宿主细胞结合时，AnkA易位到宿主细胞质中，然后迅速酪氨酸磷酸化（在数秒至数分钟内）。酪氨酸磷酸化允许AnkA结合宿主细胞中关键信号蛋白的SH2结构域。此外，AnkA还可以通过SH3结构域和锚蛋白重复序列结合蛋白质。通过这些假定的蛋白质相互作用，AnkA可能改变宿主细胞信号传导并引起中性粒细胞的细胞变化。目的1旨在确定与AnkA结合的宿主细胞蛋白的特异性相互作用。目的2提出研究AnkA在抑制中性粒细胞杀伤中的作用。目的3探讨AnkA在中性粒细胞凋亡延迟中的作用。长期目标是：1）确定A.嗜中性粒细胞中的嗜吞噬细胞菌，2）开发操纵嗜中性粒细胞的新途径，导致炎症或感染的潜在新治疗，和3）增强我们对嗜中性粒细胞生物学的理解，因为它涉及免疫系统。公共卫生相关性：人粒细胞埃里希体病，由A。嗜吞噬细胞菌是美国第二大常见的蜱相关疾病。本文试图研究A.嗜吞噬细胞菌可以在中性粒细胞中存活。这可能会导致更好地了解中性粒细胞在免疫系统中的功能，并可能导致炎症和感染的潜在新治疗方法。