A. phagocytophilum and NF-kB signaling

A. 吞噬细胞和 NF-kB 信号传导

• 批准号: 7905002
• 负责人: JOHN STEPHEN Dumler
• 金额: $ 24.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7905002
• 关键词: Adhesions; Affect; Anaplasma phagocytophilum; Anaplasmataceae; Apoptosis; Bacteria; Blood Cells; Bovine Anaplasmosis; Cell Survival; Cell physiology; Cells; Data; Disease; Endothelium; Family; Functional disorder; Future; Gene Proteins; Gene Silencing; Gene Silencing Pathway; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Goals; Growth; Host Defense; Human; Human Genome; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Integrins; Investigation; Lead; Life; Link; Longevity; Mediating; Metalloproteases; Modeling; NF-kappa B; Organism; Pathogenesis; Pathway interactions; Phagocytes; Phagocytosis; Population; Prevention approach; Prevention therapy; Publishing; Research; Respiratory Burst; Rickettsia; Rickettsiales; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Stimulus; Testing; Tick-Borne Diseases; Tick-Borne Infections; Ticks; Tissues; Up-Regulation; Vascular Permeabilities; antimicrobial; cell injury; cell motility; chemokine; combat; cost; cytokine; granulocyte; in vivo; inhibitor/antagonist; insight; member; microbial; microbicide; neutrophil; pathogen; public health relevance; response

DESCRIPTION (provided by applicant): Human granulocytic anaplasmosis (HGA) is tick-borne disease caused by Anaplasma phagocytophilum, an obligate intracellular bacterium of neutrophils. A. phagocytophilum subverts host granulocyte functions, deactivating antimicrobial function and activating proinflammatory response. The "activated-deactivated" neutrophil promotes recruitment of new host cells and tissue injury, but is unable to generate effective antimicrobial responses. We demonstrated a bacterial advantage to new host cell recruitment with chemokine gene upregulation and, analogously, any up-modulation of inflammation could benefit the bacterium. Inflammatory response is mediated through NF-?B signaling, which is significantly upregulated with A. phagocytophilum, whose survival likely depends on subversion of this pathway. We hypothesize that upregulated NF-?B signaling in A. phagocytophilum-infected neutrophils: 1) is critical for pathogen survival and dependent upon active infection, and 2) leads to subverted neutrophil functions that benefit the pathogen but belie cell/tissue injury. Thus, we propose: 1. To show a role for NF-?B signaling in A. phagocytophilum growth enhancement and/or altered neutrophil function that permit bacterial survival and propagation. Inhibited pathways and silenced genes that suppress A. phagocytophilum propagation will identify critical high priority targets genes, proteins, pathways and/or functions targeted by the bacterium. 2. To discern the altered neutrophil/granulocyte proinflammatory functions that result from A. phagocytophilum-associated subversion of host cells and permit neutrophil-mediated tissue injury. These data will link specific A. phagocytophilum-altered pathways with proinflammatory neutrophil function alterations to determine their role in pathogenesis and disease. This will eventually facilitate the search for bacterial effectors translocated into the host that mediate neutrophil function changes and belie tissue injury, inflammation and disease. Our long-term goals are to understand the mechanisms by which obligate intracellular bacteria exploit host cells for survival. The short-term objective is to identify likely host targets of A. phagocytophilum effectors that enhance inflammatory response and pathogen survival. Such studies will yield important clues about the HGA pathogenesis to advance in-depth investigation and will provide broad information about neutrophil function in some inflammatory and infectious states. PUBLIC HEALTH RELEVANCE: Human granulocytic anaplasmosis is an emerging tick-borne infection that can be mild or fatal. Research indicates that the bacterium, which must live inside of a blood cell, causes the infection by changing its host blood cell to favor bacterial survival, in part by increasing inflammation signals. This application proposes to examine in detail the proteins, genes, and pathways by which inflammation is increased, and whether this truly promotes survival of the pathogen. This could lead to new information on how disease occurs with this organism and others, and perhaps new information about ways to combat this infection or to change host cell function in other diseases.

描述（由申请方提供）：人粒细胞无形体病（HGA）是由嗜吞噬细胞无形体（嗜中性粒细胞的专性细胞内细菌）引起的蜱媒疾病。A.嗜吞噬细胞菌破坏宿主粒细胞功能，使抗微生物功能失活并激活促炎反应。“活化-失活”的中性粒细胞促进新宿主细胞的募集和组织损伤，但不能产生有效的抗菌反应。我们证明了细菌在趋化因子基因上调的情况下对新宿主细胞募集的优势，类似地，任何炎症的上调都可能使细菌受益。炎症反应是通过NF-？B信号传导，其被A显著上调。嗜吞噬细胞菌，其存活可能取决于该途径的破坏。我们假设上调NF-？A中的B信号。嗜吞噬细胞菌感染的中性粒细胞：1）对于病原体存活至关重要并且依赖于活动性感染，以及2）导致破坏的中性粒细胞功能，其有益于病原体但掩盖细胞/组织损伤。因此，我们建议： 1.为了给NF-？A中的B信号。嗜吞噬细胞生长增强和/或改变的嗜中性粒细胞功能，其允许细菌存活和繁殖。抑制途径和沉默基因，抑制A。嗜吞噬细胞菌繁殖将鉴定细菌靶向的关键高优先级靶基因、蛋白质、途径和/或功能。 2.目的：观察A.嗜吞噬细胞相关的宿主细胞的颠覆，并允许嗜吞噬细胞介导的组织损伤。这些数据将连接特定的A。嗜吞噬细胞改变的途径与促炎中性粒细胞功能改变，以确定它们在发病机制和疾病中的作用。这最终将有助于寻找转移到宿主中的细菌效应子，这些细菌效应子介导中性粒细胞功能的变化，并掩盖组织损伤、炎症和疾病。 我们的长期目标是了解专性细胞内细菌利用宿主细胞生存的机制。短期目标是确定A.嗜吞噬细胞效应子，增强炎症反应和病原体存活。这些研究将产生关于HGA发病机制的重要线索，以推进深入研究，并将提供有关中性粒细胞在某些炎症和感染状态下功能的广泛信息。公共卫生相关性：人粒细胞无形体病是一种新出现的蜱传感染，可能是轻度或致命的。研究表明，这种细菌必须生活在血细胞内，通过改变宿主血细胞以利于细菌存活，部分通过增加炎症信号来引起感染。该应用程序提出详细检查增加炎症的蛋白质，基因和途径，以及这是否真的促进了病原体的存活。这可能会带来关于这种生物体和其他生物体如何发生疾病的新信息，也许还会带来关于如何对抗这种感染或改变其他疾病中宿主细胞功能的新信息。