Regulatory targets and pathogenic mechanisms of anthrax edema factor

炭疽水肿因子的调控靶点及致病机制

• 批准号: 7677955
• 负责人: Jin Mo Park
• 金额: $ 39.13万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677955
• 关键词: Adenylate Cyclase; Animal Model; Anthrax disease; Antigens; Bacillus anthracis; Bacteria; Binding Sites; Blood Circulation; Blood Vessels; CREB1 gene; Cells; Cleaved cell; Communicable Diseases; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytosol; DNA Microarray Chip; Data; Disease; Edema; Employee Strikes; Event; Exhibits; Experimental Models; Fibrinogen; Fostering; Gene Expression; Gene Targeting; Genes; Goals; Growth; Human; Immune system; In Vitro; Infection; Kinetics; Lead; Link; Lymph; Lymphangiogenesis; Lymphatic; Mediating; Metalloproteases; Methods; Microarray Analysis; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Mus; N-terminal; Participant; Pathogenesis; Pathologic; Play; Process; Production; Promoter Regions; Proteins; Research; Role; Signal Transduction; Surface; System; Systemic infection; Testing; Toxin; Upper arm; Vascular Endothelial Growth Factors; Vascular Permeabilities; analog; anthrax edema factor; anthrax lethal factor; antigen binding; base; cell motility; cytokine; edema factor; in vivo; insight; lymph nodes; macrophage; migration; mouse model; novel; novel therapeutics; polypeptide; prevent; public health relevance; receptor; response; transcription factor

DESCRIPTION (provided by applicant): Bacillus anthracis, the causative agent of anthrax, produces three toxin polypeptides: protective antigen (PA), lethal factor (LF) and edema factor (EF). PA binds to receptors expressed on the surface of host cells and allows cellular entry of LF and EF. The function of LF in anthrax pathogenesis has been extensively studied by investigating its action in both cultured macrophages and animal models. By contrast, very little is known about the regulatory targets and pathogenic mechanism of EF. We found that EF, with its adenylate cyclase activity, promotes motility and survival of macrophages in vitro. Our preliminary data also suggest that EF suppresses production of certain proinflammatory cytokines while activating a number of novel target genes that include the cytokine vascular endothelial growth factor (VEGF). VEGF is known to increase vascular permeability, thereby causing edema, and also promote the growth of lymphatic and blood vessels. Based on these findings, we propose that EF may play a role in accelerating the migration of B. anthracis-infected macrophages to lymph nodes and spreading of the bacterium to the blood circulation. To test this idea, we plan to pursue the following specific aims: 1) Identify the transcription factors that link cAMP signaling to the expression of EF target genes in macrophages; 2) Determine the mechanisms by which EF promotes macrophage motility and survival; and 3) Determine the mechanisms by which EF activates VEGF expression in macrophages and lymphangiogenesis in mice. In addition to providing better insight into the mechanism of anthrax pathogenesis, we aim at devising an efficient method to prevent the spreading of B. anthracis toward fatal systemic infection by modulating the function of EF-targeted host proteins. PUBLIC HEALTH RELEVANCE: We are investigating the mechanisms by which anthrax bacteria manipulate macrophages, major cell participants in the first-strike arm of the immune system, disturbing the signaling system and commandeering the cells as transport, thus allowing the bacteria to spread in the body. Using cultured macrophage cells and mice, we will study exactly how edema factor, one of the toxin proteins produced by anthrax bacteria, activates host genes and thereby directs the spreading of this deadly bacterium. Our hope is that these efforts will lead to the discovery of new targets for the treatment of anthrax and other infectious diseases.

性状（由申请人提供）：炭疽芽孢杆菌是炭疽的病原体，产生三种毒素多肽：保护性抗原（PA）、致死因子（LF）和水肿因子（EF）。PA与宿主细胞表面表达的受体结合，并允许LF和EF进入细胞。LF在炭疽发病机制中的作用已经通过研究其在培养的巨噬细胞和动物模型中的作用而被广泛研究。与此相反，对EF的调控靶点和致病机制知之甚少。我们发现，EF，其腺苷酸环化酶活性，促进运动和巨噬细胞在体外的生存。我们的初步数据还表明，EF抑制某些促炎细胞因子的产生，同时激活一些新的靶基因，包括细胞因子血管内皮生长因子（VEGF）。已知VEGF增加血管渗透性，从而引起水肿，并且还促进淋巴管和血管的生长。基于这些发现，我们认为EF可能在加速B迁移方面发挥了作用。炭疽感染的巨噬细胞转移到淋巴结，细菌扩散到血液循环。为了验证这一想法，我们计划追求以下具体目标：1）确定将cAMP信号传导与巨噬细胞中EF靶基因表达联系起来的转录因子; 2）确定EF促进巨噬细胞运动和存活的机制; 3）确定EF激活巨噬细胞中VEGF表达和小鼠淋巴管生成的机制。除了提供更好的了解炭疽发病机制，我们的目标是设计一种有效的方法来防止B的传播。通过调节EF靶向宿主蛋白的功能，将炭疽菌引向致死性全身感染。公共卫生相关性：我们正在研究炭疽细菌操纵巨噬细胞的机制，巨噬细胞是免疫系统第一次攻击的主要细胞参与者，干扰信号系统并征用细胞作为运输工具，从而使细菌在体内传播。利用培养的巨噬细胞和小鼠，我们将研究炭疽细菌产生的毒素蛋白之一水肿因子如何激活宿主基因，从而指导这种致命细菌的传播。我们希望，这些努力将导致发现治疗炭疽和其他传染病的新目标。