A. phagocytophilum and NF-kB signaling

描述（由申请人提供）：人粒细胞无形体病（HGA）是由嗜吞噬细胞无形体引起的蜱传疾病，嗜吞噬细胞无形体是中性粒细胞的专性细胞内细菌。嗜吞噬细胞破坏宿主粒细胞功能，使抗菌功能失活并激活促炎反应。“活化-失活”中性粒细胞促进新宿主细胞的招募和组织损伤，但不能产生有效的抗菌反应。我们证明了细菌的优势，新的宿主细胞募集与趋化因子基因上调，类似地，任何上调炎症可能有利于细菌。炎症反应是通过NF-？B信号，该信号在嗜吞噬细胞芽胞杆菌中显著上调，其存活可能依赖于该途径的破坏。我们假设上调的NF-？嗜吞噬细胞感染的中性粒细胞中的B信号：1)对病原体存活至关重要，依赖于主动感染；2)导致中性粒细胞功能被破坏，有利于病原体，但导致细胞/组织损伤。因此，我们建议：

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.