JC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells
JC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells
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DOI：
10.1128/mbio.00379-19
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发表时间：
2019-03-01
期刊：
影响因子：
6.4
通讯作者：
Atwood, Walter J.
中科院分区：
文献类型：
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作者：
Morris-Love, Jenna;Gee, Gretchen V.;Atwood, Walter J.
地方性人JC多瘤病毒（JCPyV）在免疫抑制患者中引起进行性多灶性白质脑病。体内病毒感染的机制尚不清楚，因为脑中病毒的主要靶细胞不表达病毒受体，也不结合病毒。我们发现JCPyV与细胞外囊泡（EV）相关联，并且可以独立于病毒受体感染靶细胞。病毒颗粒被包装在细胞外囊泡内，并附着在囊泡的外侧。抗JCPyV抗血清减少了纯化病毒的感染，但对EV相关病毒的感染没有影响。用受体破坏酶神经氨酸酶处理细胞可抑制纯化病毒的感染，但不能抑制EV相关病毒的感染。唾液酸受体结合缺陷的突变假病毒不能将细胞作为纯化的假病毒粒子，但当与EV结合时可以这样做。这种替代感染机制可能在JCPyV向中枢神经系统和在中枢神经系统内的传播和扩散中起着关键作用。重要性JC多瘤病毒（JCPyV）是一种普遍存在的人类病原体，可导致进行性多灶性白质脑病（PML），这是一种严重且通常致命的免疫功能低下或免疫调节患者的神经退行性疾病。在易感细胞中引发感染的机制尚不完全清楚。该病毒的主要附着受体，乳系列四糖c（LSTc），矛盾的是不表达在人脑中的少突胶质细胞或星形胶质细胞上，并且病毒不结合这些细胞。因为这些是病毒在大脑中靶向的主要细胞类型，我们假设感染的替代机制必须负责。在这里，我们提供的证据表明，JCPyV是包装在细胞外囊泡从感染的细胞。囊泡相关病毒对靶细胞的感染不依赖于LSTc，也不被针对该病毒的抗血清中和。这是首次证明多瘤病毒使用细胞外囊泡作为传播方式。
The endemic human JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy in immune-suppressed patients. The mechanisms of virus infection in vivo are not understood because the major target cells for virus in the brain do not express virus receptors and do not bind virus. We found that JCPyV associates with extracellular vesicles (EVs) and can infect target cells independently of virus receptors. Virus particles were found packaged inside extracellular vesicles and attached to the outer side of vesicles. Anti-JCPyV antisera reduced infection by purified virus but had no effect on infection by EV-associated virus. Treatment of cells with the receptor-destroying enzyme neuraminidase inhibited infection with purified virus but did not inhibit infection by EV-associated virus. Mutant pseudoviruses defective in sialic acid receptor binding could not transduce cells as purified pseudovirions but could do so when associated with EVs. This alternative mechanism of infection likely plays a critical role in the dissemination and spread of JCPyV both to and within the central nervous system.IMPORTANCE JC polyomavirus (JCPyV) is a ubiquitous human pathogen that causes progressive multifocal leukoencephalopathy (PML), a severe and often fatal neurodegenerative disease in immunocompromised or immunomodulated patients. The mechanisms responsible for initiating infection in susceptible cells are not completely known. The major attachment receptor for the virus, lactoseries tetrasaccharide c (LSTc), is paradoxically not expressed on oligodendrocytes or astrocytes in human brain, and virus does not bind to these cells. Because these are the major cell types targeted by the virus in the brain, we hypothesized that alternative mechanisms of infection must be responsible. Here we provide evidence that JCPyV is packaged in extracellular vesicles from infected cells. Infection of target cells by vesicle-associated virus is not dependent on LSTc and is not neutralized by antisera directed against the virus. This is the first demonstration of a polyomavirus using extracellular vesicles as a means of transmission.