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（由申请人提供）：人类粒细胞肿瘤病（HGA）是由吞噬吞噬细胞吞噬引起的tick传播疾病，这是一种强性的嗜中性粒细胞的细胞内细菌。 A.吞噬细胞噬菌体颠覆宿主粒细胞功能，抗菌功能并激活促炎反应。 “活化的二次活化”中性粒细胞促进了新的宿主细胞和组织损伤的募集，但无法产生有效的抗菌反应。我们证明了趋化因子基因上调的新宿主细胞募集具有细菌优势，并且类似地，任何炎症的上调节都可以使细菌受益。炎症反应是通过NF-？b信号传导介导的，吞噬细胞嗜血杆菌的生存可能取决于该途径的颠覆，这显着上调。我们假设在吞噬细胞感染的嗜中性粒细胞中上调NF-？b信号传导：1）对于病原体存活和依赖于主动感染至关重要，并且2）导致颠覆性的中性粒细胞功能，使病原体受益，但相信细胞/组织损伤。因此，我们提出： 1。显示NF-？B信号传导在吞噬细胞的生长增强和/或中性粒细胞功能中的作用，以允许细菌生存和传播。抑制抑制吞噬细胞噬菌体传播的途径和沉默基因将确定细菌靶向的基因，蛋白质，途径和/或功能的关键高优先级靶标。 2。辨别嗜中性粒细胞/粒细胞促炎性功能的改变，这是由吞噬细胞杆菌相关的宿主细胞颠覆并允许中性粒细胞介导的组织损伤引起的。这些数据将将特定的吞噬细胞藻虫的途径与促炎性嗜中性粒细胞功能改变联系起来，以确定它们在发病机理和疾病中的作用。最终，这将促进迁移到介导中性粒细胞功能变化并相信组织损伤，炎症和疾病的宿主中的细菌效应子。 我们的长期目标是了解义务细胞内细菌利用宿主细胞生存的机制。短期目的是确定吞噬细胞杆菌效应子的可能宿主靶标，从而增强炎症反应和病原体存活率。此类研究将产生有关HGA发病机理的重要线索，以提高深入研究，并在某些炎症和传染性状态下提供有关中性粒细胞功能的广泛信息。公共卫生相关性：人类粒细胞肿瘤病是一种新兴的tick传播感染，可能是轻度或致命的。研究表明，必须生活在血细胞内部的细菌通过改变其宿主血细胞以有利于细菌生存的细菌，部分原因是增加了炎症信号。该应用建议详细检查炎症增加的蛋白质，基因和途径，以及这是否真正促进了病原体的生存。这可能会导致有关该生物和其他生物如何发生疾病的新信息，以及有关对抗这种感染或改变其他疾病中宿主细胞功能的方法的新信息。