mBio：研究表明神经性疾病或与感染疱疹病毒有关

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多年来，研究者发现，神经疾病和某些特定类型的疱疹病毒之间有关联。在阿尔兹海默症、多发性硬化症、小脑性共济失调以及其它一些神经疾病中，患者脑脊液中有很多的Epstein-Barr病毒（EBV，人类疱疹病毒第四型）。但是，其中的本质还尚不清楚。因为人们一直认为EBV以及其它一些同类型的病毒（γ-疱疹病毒）不会感染神经细胞。

如今，宾夕法尼亚大学佩雷尔曼医学院的研究者们让我们深入了解了其中的奥妙。Abramson癌症研究中心肿瘤病毒学的主任Erle S. Robertson博士及他的同事们于本周在mBio杂志上发表了一篇研究，EBV以及相关的病毒（KSHV）可以感染人的初级神经元，并且能在里面进行复制。

尽管没有证明其中的缘由，但是这些数据确实表明了，病毒性感染能够导致大脑疾病的某些症状，也为抗病毒药治疗神经性疾病提供了依据。

根据Robertson，γ-疱疹病毒可能会感染脑组织。首先，病毒聚集在MS患者或者阿尔兹海默症患者的脑脊液和大脑组织中。另外，那些曾经由于EBV感染而患传染性单核细胞增多症的患者，如今患MS的几率更高；从未感染EBV的人患MS的几率低很多。特别明显的是，能抑制EBV和相关病毒的药物，阿昔洛韦能够作为MS的潜在治疗方法，并且效果不错。

Robertson还表示，γ-疱疹病毒感染神经细胞的能力众说纷纭。Devan Mehta，Robertson实验室的学生，他同Hem C.Jha博士、Dennis Kolson博士一起验证了其中的关联。利用能表达绿色荧光蛋白(GFP)的转基因病毒，Mehta感染了人类神经母细胞瘤细胞（从癌细胞中分离出的神经细胞）以及胎儿神经细胞，通过显微镜观察蛋白表达监测感染情况。

两种类型的细胞中，不论是感染EBV还是感染KSHV都会出现荧光信号，也会表达出病毒蛋白。培养被感染细胞的媒介中也出现了病毒粒子，说明这些感染确实侵占了宿主细胞。另外，用阿昔洛韦进行治疗能够限制病毒粒子的产生。

“真是难以置信啊，”Robertson表示。“EBV研究了50年，从来没人在神经细胞中发现过。或许只是他们没查看过而已。”

为什么EBV和KSHV感染神经细胞会导致如此严重的疾病，在以后的研究中将进一步探究。相反，当这些病毒感染其它类型的细胞时，例如B细胞，病毒粒子是处于休眠状态的。但是，当它们感染神经细胞时，这些病毒粒子就会产生大量的病毒，导致神经细胞的破裂、死亡，这就是培养被感染细胞的媒介还能感染其它细胞的原因。

来源：来宝网

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Gammaherpesvirus Infection of Human Neuronal Cells

Hem Chandra Jha, Devan Mehta, Jie Lua, Darine El-Naccache, Sanket K. Shukla, Colleen Kovacsics, Dennis Kolson, Erle S. Robertson

ABSTRACT
Gammaherpesviruses human herpesvirus 4 (HHV4) and HHV8 are two prominent members of the herpesvirus family associated with a number of human cancers. HHV4, also known as Epstein-Barr virus (EBV), a ubiquitous gammaherpesvirus prevalent in 90 to 95% of the human population, is clinically associated with various neurological diseases such as primary central nervous system lymphoma, multiple sclerosis, Alzheimer’s disease, cerebellar ataxia, and encephalitis. However, the possibility that EBV and Kaposi’s sarcoma-associated herpesvirus (KSHV) can directly infect neurons has been largely overlooked. This study has, for the first time, characterized EBV infection in neural cell backgrounds by using the Sh-Sy5y neuroblastoma cell line, teratocarcinoma Ntera2 neurons, and primary human fetal neurons. Furthermore, we also demonstrated KSHV infection of neural Sh-Sy5y cells. These neuronal cells were infected with green fluorescent protein-expressing recombinant EBV or KSHV. Microscopy, genetic analysis, immunofluorescence, and Western blot analyses for specific viral antigens supported and validated the infection of these cells by EBV and KSHV and showed that the infection was efficient and productive. Progeny virus produced from infected neuronal cells efficiently infected fresh neuronal cells, as well as peripheral blood mononuclear cells. Furthermore, acyclovir was effective at inhibiting the production of virus from neuronal cells similar to lymphoblastoid cell lines; this suggests active lytic replication in infected neurons in vitro. These studies represent a potentially new in vitro model of EBV- and KSHV-associated neuronal disease development and pathogenesis.

IMPORTANCE
To date, no in vitro study has demonstrated gammaherpesvirus infection of neuronal cells. Moreover, worldwide clinical findings have linked EBV to neuronal pathologies, including multiple sclerosis, primary central nervous system lymphoma, and Alzheimer’s disease. In this study, for the first time, we have successfully demonstrated the in vitro infection of Sh-Sy5y and Ntera2 cells, as well as human primary neurons. We have also determined that the infection is predominately lytic. Additionally, we also report infection of neuronal cells by KSHV in vitro similar to that by EBV. These findings may open new avenues of consideration related to neuronal pathologies and infection with these viruses. Furthermore, their contribution to chronic infection linked to neuronal disease will provide new clues to potential new therapies.

http://mbio.asm.org/content/6/6/e01844-15