Anaplasma regulation of host granulocyte functions

描述（由申请人提供）：人粒细胞无形体病（HGA，以前的HGE）是由嗜吞噬细胞无形体引起的一种新出现的蜱传感染，嗜吞噬细胞无形体是中性粒细胞的专性细胞内寄生虫。患者会患上一种“流感样”疾病，严重时会出现休克或呼吸窘迫。死亡是罕见的，但异常的宿主免疫和炎症可导致机会性感染。受感染的中性粒细胞同时被“激活”和“失活”，导致不协调的促炎反应，有利于受感染细胞的积累和杀微生物和调节能力的丧失。受感染的中性粒细胞减少了一些宿主基因的转录效应机制和细胞周期。嗜吞噬胞杆菌AnkA蛋白从寄生液泡中转运到宿主细胞核中积累，这是已知的唯一进入细胞的细菌蛋白。此外，AnkA结合宿主DNA和蛋白质，特别是结合已知显著影响染色体上50至100 kb范围内基因转录的基质附着区域。因此，我们建议AnkA：

DESCRIPTION (provided by applicant): Human granulocytic anaplasmosis (HGA, formerly HGE) is an emerging tick-borne infection caused by Anaplasma phagocytophilum, an obligate intracellular parasite of neutrophils. Patients develop a "flu-like" illness that can be severe with shock or respiratory distress. Death is infrequent, but abnormal host immunity and inflammation can lead to opportunistic infections. Infected neutrophils are simultaneously "activated" and "deactivated" resulting in a discoordinated proinflammatory response favoring infected cell accumulation and loss of microbicidal and regulatory capacity. Infected neutrophils have diminished transcription of some host genes for effector mechanisms and cell cycling. A. phagocytophilum AnkA protein is ferried from the parasitophorous vacuole to accumulate in the host cell nucleus, where it is the only known protein of the bacterium to enter the cell. Moreover, AnkA binds both host DNA and proteins, and binds particularly to matrix attachment regions that are known to significantly influence transcription of genes within 50 to 100 kb on the chromosome. Thus, we propose AnkA: 1. is rapidly transcribed and transported to the granulocyte nucleus; 2. mediates some of the neutrophil functional changes with A. phagocytophilum infection; 3. directly interacts with host cell chromatin to influence the transcription of host genes. We propose to i) describe the kinetics of ankA transcription and AnkA expression, and to examine whether other genes in proximity to ankA in the A. phagocytophilum genome are coordinately regulated; ii) characterize the effects of AnkA on neutrophil function; iii) demonstrate how A. phagocytophilum infection or AnkA affect transcription of key genes and neutrophil function by AnkA binding to specialized ATC chromatin structures, modification of chromatin architecture and change in gene transcription at specific loci, with special emphasis on CYBB, RAC2, and IL8. Thus, we will evaluate how A. phagocytophilum and AnkA regulate gene transcription and consequently neutrophil function. The proposed model of control is not yet described for any bacterium and would provide a novel mechanism for bacterial control of infected hosts. These studies will provide a model for understanding how the bacterium lives in and subverts neutrophils and should improve comprehension of disease pathogenesis. With this will come a strategy for design of prevention, management, and treatment of HGA, and a new model for investigating the neutrophil biology.