Pathogenic interaction of enterovirus 71 with PSGL-1 on human leukocytes

描述（由申请人提供）：肠病毒71 （EV71）引起儿童手足口病（HFMD）。与仅引起轻度手足口病的相关病毒不同，EV71还会引起严重的神经系统疾病和死亡——最常见的原因是肺水肿和心肺衰竭。亚洲最近的流行病影响了数百万儿童，给医疗保健系统带来沉重负担，并造成数千人死亡。为什么有些儿童患有严重的神经系统疾病或肺水肿尚不清楚，但肺水肿和致命的结局与高水平的炎症细胞因子有关。我们认为其中一个关键因素可能是特异性EV71分离株对p选择素糖蛋白配体-1 （PSGL-1）的趋向性，这是一种几乎只在血细胞上表达的信号受体。PSGL-1介导白细胞粘附在血管壁上的选择素上(6)，PSGL-1的参与启动了一系列细胞内事件，促进白细胞粘附和迁移到组织中，并导致免疫细胞产生细胞因子和趋化因子。这一应用背后的假设是，病毒与白细胞上的PSGL-1相互作用在严重EV71疾病的发病机制中很重要，因为它允许病毒进入并感染特定的白细胞群，并且因为它触发PSGL-1介导的信号，这些信号有助于白细胞活化、粘附/迁移和细胞因子的产生。我们将对此进行测试

DESCRIPTION (provided by applicant): Enterovirus 71 (EV71) causes hand-foot-mouth disease (HFMD) in children. Unlike related viruses that cause only mild HFMD, EV71 also causes severe neurologic disease, and death- most often due to pulmonary edema and cardiorespiratory failure. Recent epidemics in Asia have affected millions of children, putting a heavy burden on the healthcare system, and causing thousands of deaths. Why some children suffer severe neurologic disease or pulmonary edema is not known, but pulmonary edema and fatal outcome are associated with high levels of inflammatory cytokines. We believe that one critical factor may be the tropism of specific EV71 isolates for P-selectin glycoprotein ligand-1 (PSGL-1), a signaling receptor almost exclusively expressed on blood cells. PSGL-1 mediates the tethering of leukocytes to selectins on vessel walls (6), and PSGL-1 engage- ment initiates a series of intracellular events that promote leukocyte adhesion adhesion and migration into tissues, and lead to the production of cytokines and chemokines by immune cells. The hypothesis underlying this application is that virus interaction with PSGL-1 on leukocytes is important in the pathogenesis of severe EV71 disease, both because it permits virus to enter and infect specific leukocyte populations, and because it triggers PSGL-1-mediated signals that contribute to leukocyte activation, adhesion/migration, and cytokine production. We will test this hypothesis in three sets of experiments. First, we will identify leukocyte subsets that are bound or infected by EV71 in a PSGL-1-dependent manner, and determine whether virus binding or infection leads to immune cell activation, adhesion, or cytokine production. Second, we will determine whether EV71 interaction with leukocytes stimulates the passage of virus and inflammatory cells across an in vitro model of the blood-brain barrier. Finally, in collaboration with investigators at the Pasteur institute of Shanghai, we well determine whether PSGL-1-binding viruses have increased pathogenic potential, by examining virus isolates obtained from children with severe and mild EV71 disease.