EHRLICHIA-GRANULOCYTE INTERACTIONS AND INFECTION

埃里克体-粒细胞相互作用和感染

• 批准号: 6044310
• 负责人: JOHN STEPHEN Dumler
• 金额: $ 23.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044310
• 关键词: Ehrlichia; bacteria infection mechanism; bacterial proteins; cell membrane; cytokine; ehrlichiosis; granulocyte; leukocyte activation /transformation; tissue /cell culture

DESCRIPTION (Adapted from the Applicant's Abstract): Human Granulocytic Ehrlichiosis (HGE) is a recently emergent tick-transmitted infectious disease that has been reported with increasing frequency during the last decade. The causative agent is classified within the ehrlichial genogroup II and is considered to be a variant or subspecies of Ehrlichia phagocytophila. Although many and perhaps most of the human infections are either subclinical or resolve without diagnosis, severe disease does result in prolonged hospitalization with intensive care and can progress to cause death. The manifestations of human disease are not specific but may manifest as a toxic shock-like illness, adult respiratory distress syndrome (ARDS), and fatal cases have an association with opportunistic infections. A similar association has been reported with the domestic animals infected by E. phagocytophila group organisms. The natural target cell is primarily neutrophils, although premyelocytic cells can be infected in vitro and myeloid progenitors have been hypothesized to be a site of infection in vivo. In contrast, infection of macrophages and monocyte-like cell lines is abortive and the organisms are killed. Interestingly, the severity of disease in humans does not reflect a high circulating ehrlichial load. Previous data from animals infected with E. phagocytophila indicates impaired neutrophil function - including chemotaxis, phagocytosis, and killing. These "deactivation" phenotypes may be concomitantly associated with "activation" in which binding to endothelial cells occurs and culminates in release of proinflammatory cytokines by endothelial cells and especially macrophages, leading to the triggering of a toxic-shock like injury. The PI proposes the following hypotheses: 1) E. phagocytophila group ehrlichiae bind to CD15-associated granulocyte surface receptors and initiate endocytosis via their major surface protein (MSP) antigens; 2) Binding, internalization, and propagation of E. phagocytophila group ehrlichiae initiate cytokine/chemokine expression and changes in granulocyte activation/inactivation and function; and 3): E. phagocytophila group ehrlichiae potentially influence host cell function by expressing proteins that directly interact with DNA regulatory components in the host cell's chromosomes. These hypotheses will be tested using five specific aims: i) demonstrate the morphology of the ehrlichia-host cell membrane interaction in HL60 cells in various differentiated states; ii) characterize the role of E. phagocytophila group MSPs as adhesins and the role of CD15-associated structures as the major surface receptors by which ehrlichiae attach and enter cells; iii) characterize the effects of ehrlichial binding and internalization on host granulocyte cell surface adhesion molecule expression, granulocyte-endothelial cell adherence, phagocytic activity, activation/deactivation, microbial killing, and cytokine/chemokine expression; and iv) identify the chromosomal ligand for the E. phagocytophila group ankyrin protein, EPANK1.

描述（改编自申请人摘要）：人粒细胞 埃立克体病（HGE）是近年来出现的一种蜱传传染病 在过去十年中，报告的频率越来越高。的 病原体被分类在埃里希体基因组II内， 被认为是嗜吞噬细胞埃立克体的变体或亚种。虽然 许多，也许是大多数人类感染是亚临床或解决 如果没有诊断，严重的疾病确实会导致住院时间延长， 重症监护，并可能导致死亡。人类的表现形式 疾病不是特定的，但可能表现为中毒性休克样疾病，成人 呼吸窘迫综合征（ARDS）和致命病例与 机会性感染据报道， 家畜感染E.嗜吞噬细胞群生物。自然 靶细胞主要是中性粒细胞，尽管早幼粒细胞也可以是 体外感染和髓系祖细胞已被假设为是一个网站 体内感染。相反，巨噬细胞和单核细胞样 细胞系败育，生物体被杀死。有趣的是 人类疾病的严重程度并不反映高循环埃里希体 即可.先前的数据来自感染E.嗜吞噬细胞性表明 中性粒细胞功能受损-包括趋化性、吞噬作用和杀伤作用。 这些“失活”表型可能伴随着 “激活”，其中发生与内皮细胞的结合，并在 内皮细胞释放促炎细胞因子， 巨噬细胞，导致触发毒性休克样损伤。 PI提出以下假设：1）E.嗜吞噬细胞埃立克体群 与CD 15相关的粒细胞表面受体结合并启动内吞作用 通过它们的主要表面蛋白（MSP）抗原; 2）结合，内化， 以及E.嗜吞噬细胞群埃立克体起始 细胞因子/趋化因子表达和粒细胞中的变化 激活/失活和功能;和3）：E.嗜吞噬细胞群 埃里希体通过表达 直接与宿主细胞中的DNA调节成分相互作用， 染色体这些假设将使用五个具体目标进行测试： 展示了埃立克体-宿主细胞膜相互作用的形态学， HL 60细胞在各种分化状态; ii）表征E. 嗜吞噬细胞群MSPs作为粘附素的作用及CD 15相关 作为埃立克体附着和进入的主要表面受体结构 iii）表征埃里希体结合和内化的影响 对宿主粒细胞表面粘附分子表达的影响， 粒细胞-内皮细胞粘附，吞噬活性， 活化/失活、微生物杀灭和细胞因子/趋化因子表达; 和iv）鉴定E.嗜吞噬细胞群锚蛋白 蛋白，EPANK 1。