Department of Neuroscience and Center for Neurovirology, Temple University Lewis Katz School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
J Neuroimmune Pharmacol. 2018 Jun;13(2):126-142. doi: 10.1007/s11481-017-9770-5. Epub 2017 Nov 20.
JC virus (JCV) is a human polyomavirus and the etiologic agent of the demyelinating disease progressive multifocal leukoencephalopathy (PML). PML is observed in patients with underlying immunocompromising conditions, suggesting that neuro-immune interactions between peripheral immune cells and neuro-glia play an important role in controlling viral reactivation in the brain. There is little known about the immunobiology of JCV reactivation in glial cells and the role of immune, glial, and viral players in this regulation. We have previously showed that agnoprotein, a small JCV regulatory protein, is released from infected cells and internalized by neighboring bystander cells. Here we have investigated the possible role of extracellular and intracellular agnoprotein in the neuroimmune response to JC virus. Our findings suggest that glial cells exposed to agnoprotein secrete significantly less GM-CSF, which is mediated by agnoprotein induced suppression of GM-CSF transcription. Likewise, monocytes treated with agnoprotein showed altered differentiation and maturation. In addition, monocytes and microglial cells exposed to agnoprotein showed a significant reduction in their phagocytic activities. Moreover, when an in vitro blood-brain barrier model was used, agnoprotein treatment resulted in decreased monocyte migration through the endothelial cell layer in response to activated astrocytes. All together, these results have revealed a novel immunomodulatory function of agnoprotein during JCV infection within theCNS and open a new avenue of research to better understand the mechanisms associated with JCV reactivation in patients who are at risk of developing PML.
JC 病毒（JCV）是一种人类多瘤病毒，也是脱髓鞘疾病进行性多灶性白质脑病（PML）的病原体。PML 发生于存在潜在免疫功能低下的患者中，这表明外周免疫细胞和神经胶质细胞之间的神经免疫相互作用在控制大脑中病毒的重新激活方面发挥着重要作用。关于胶质细胞中 JCV 重新激活的免疫生物学以及免疫、神经胶质和病毒在这种调控中的作用，目前知之甚少。我们之前曾表明，小 JCV 调节蛋白 agnoprotein 从受感染的细胞中释放出来，并被邻近的旁观者细胞内化。在这里，我们研究了细胞外和细胞内 agnoprotein 在针对 JC 病毒的神经免疫反应中可能发挥的作用。我们的研究结果表明，暴露于 agnoprotein 的神经胶质细胞会显著减少 GM-CSF 的分泌，这是由 agnoprotein 诱导的 GM-CSF 转录抑制所介导的。同样，用 agnoprotein 处理的单核细胞显示出分化和成熟的改变。此外，暴露于 agnoprotein 的单核细胞和小神经胶质细胞的吞噬活性显著降低。此外，当使用体外血脑屏障模型时，agnoprotein 处理会导致激活的星形胶质细胞反应下穿过内皮细胞层的单核细胞迁移减少。总之，这些结果揭示了 agnoprotein 在中枢神经系统内 JCV 感染过程中的一种新的免疫调节功能，并为更好地理解与 PML 风险患者中 JCV 重新激活相关的机制开辟了新的研究途径。
