Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, United States of America.
Graduate Program in Pathobiology, Brown University, Providence, Rhode Island, United States of America.
PLoS Pathog. 2020 Mar 4;16(3):e1008371. doi: 10.1371/journal.ppat.1008371. eCollection 2020 Mar.
The human polyomavirus, JCPyV, is the causative agent of progressive multifocal leukoencephalopathy (PML) in immunosuppressed and immunomodulated patients. Initial infection with JCPyV is common and the virus establishes a long-term persistent infection in the urogenital system of 50-70% of the human population worldwide. A major gap in the field is that we do not know how the virus traffics from the periphery to the brain to cause disease. Our recent discovery that human choroid plexus epithelial cells are fully susceptible to virus infection together with reports of JCPyV infection of choroid plexus in vivo has led us to hypothesize that the choroid plexus plays a fundamental role in this process. The choroid plexus is known to relay information between the blood and the brain by the release of extracellular vesicles. This is particularly important because human macroglia (oligodendrocytes and astrocytes), the major targets of virus infection in the central nervous system (CNS), do not express the known attachment receptors for the virus and do not bind virus in human tissue sections. In this report we show that JCPyV infected choroid plexus epithelial cells produce extracellular vesicles that contain JCPyV and readily transmit the infection to human glial cells. Transmission of the virus by extracellular vesicles is independent of the known virus attachment receptors and is not neutralized by antisera directed at the virus. We also show that extracellular vesicles containing virus are taken into target glial cells by both clathrin dependent endocytosis and macropinocytosis. Our data support the hypothesis that the choroid plexus plays a fundamental role in the dissemination of virus to brain parenchyma.
人类多瘤病毒 JCPyV 是免疫抑制和免疫调节患者进行性多灶性白质脑病（PML）的病原体。JCPyV 的初次感染很常见，该病毒在全球 50-70%的人口的泌尿生殖系统中建立了长期持续性感染。该领域的一个主要空白是，我们不知道病毒如何从外周向大脑传播导致疾病。我们最近发现，人脉络丛上皮细胞容易受到病毒感染，并且有报道称 JCPyV 感染体内脉络丛，这促使我们假设脉络丛在这个过程中起着重要作用。脉络丛通过释放细胞外囊泡在血液和大脑之间传递信息，这一点尤其重要，因为人类巨噬细胞（少突胶质细胞和星形胶质细胞）是中枢神经系统（CNS）中病毒感染的主要靶标，它们不表达已知的病毒附着受体，并且在人组织切片中不结合病毒。在本报告中，我们表明 JCPyV 感染的脉络丛上皮细胞产生含有 JCPyV 的细胞外囊泡，并容易将感染传播给人类神经胶质细胞。细胞外囊泡介导的病毒传播不依赖于已知的病毒附着受体，并且不能被针对病毒的抗血清中和。我们还表明，含有病毒的细胞外囊泡通过网格蛋白依赖的内吞作用和巨胞饮作用被靶神经胶质细胞摄取。我们的数据支持这样的假设，即脉络丛在病毒向脑实质的传播中起着基础性作用。
