Holmgren Alicia M, Miller Katelyn D, Cavanaugh Sarah E, Rall Glenn F
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA Program in Blood Cell Development and Function, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Program in Blood Cell Development and Function, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA Program in Cell and Molecular Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Virol. 2015 Nov;89(21):11011-8. doi: 10.1128/JVI.01745-15. Epub 2015 Aug 26.
In permissive mouse central nervous system (CNS) neurons, measles virus (MV) spreads in the absence of hallmark viral budding or neuronal death, with transmission occurring efficiently and exclusively via the synapse. MV infection also initiates a robust type I interferon (IFN) response, resulting in the synthesis of a large number of genes, including bone marrow stromal antigen 2 (Bst2)/tetherin/CD317. Bst2 restricts the release of some enveloped viruses, but to date, its role in viral infection of neurons has not been assessed. Consequently, we investigated how Bst2 was induced and what role it played in MV neuronal infection. The magnitude of induction of neuronal Bst2 RNA and protein following IFN exposure and viral infection was notably higher than in similarly treated mouse embryo fibroblasts (MEFs). Bst2 synthesis was both IFN and Stat1 dependent. Although Bst2 prevented MV release from nonneuronal cells, its deletion had no effect on viral pathogenesis in MV-challenged mice. Our findings underscore how cell-type-specific differences impact viral infection and pathogenesis.
Viral infections of the central nervous system can lead to debilitating disease and death. Moreover, it is becoming increasingly clear that nonrenewable cells, including most central nervous system neurons, combat neurotropic viral infections in fundamentally different ways than other rapidly dividing and renewable cell populations. Here we identify type I interferon signaling as a key inducer of a known antiviral protein (Bst2) in neurons. Unexpectedly, the gene is dispensable for clearance of neurotropic viral infection despite its well-defined contribution to limiting the spread of enveloped viruses in proliferating cells. A deeper appreciation of the importance of cell type heterogeneity in antiviral immunity will aid in the identification of unique therapeutic targets for life-threatening viral infections.
在允许性小鼠中枢神经系统（CNS）神经元中，麻疹病毒（MV）在没有典型病毒出芽或神经元死亡的情况下传播，并且仅通过突触高效地进行传播。MV感染还引发强烈的I型干扰素（IFN）反应，导致大量基因的合成，包括骨髓基质抗原2（Bst2）/束缚素/ CD317。Bst2限制一些包膜病毒的释放，但迄今为止，其在神经元病毒感染中的作用尚未得到评估。因此，我们研究了Bst2是如何被诱导的以及它在MV神经元感染中发挥了什么作用。IFN暴露和病毒感染后神经元Bst2 RNA和蛋白质的诱导程度明显高于同样处理的小鼠胚胎成纤维细胞（MEF）。Bst2的合成依赖于IFN和Stat1。虽然Bst2阻止MV从非神经元细胞中释放，但其缺失对受MV攻击的小鼠的病毒发病机制没有影响。我们的研究结果强调了细胞类型特异性差异如何影响病毒感染和发病机制。
中枢神经系统的病毒感染可导致使人衰弱的疾病和死亡。此外，越来越明显的是，包括大多数中枢神经系统神经元在内的不可再生细胞，与嗜神经病毒感染作斗争的方式与其他快速分裂和可再生细胞群体根本不同。在这里，我们确定I型干扰素信号传导是神经元中一种已知抗病毒蛋白（Bst2）的关键诱导剂。出乎意料的是，尽管该基因在限制包膜病毒在增殖细胞中的传播方面有明确作用，但对于清除嗜神经病毒感染却是可有可无的。更深入地认识细胞类型异质性在抗病毒免疫中的重要性，将有助于确定危及生命的病毒感染的独特治疗靶点。
