Li Ying, Dunphy Jaclyn M, Pedraza Carlos E, Lynch Connor R, Cardona Sandra M, Macklin Wendy B, Lynch William P
Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.
Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA Programs in Neurosciences, and Cell and Molecular Biology, School of Biomedical Sciences, Kent State University, Kent, Ohio, USA.
J Virol. 2016 Jan 13;90(7):3385-99. doi: 10.1128/JVI.03156-15.
Certain murine leukemia viruses (MLVs) are capable of inducing fatal progressive spongiform motor neuron disease in mice that is largely mediated by viral Env glycoprotein expression within central nervous system (CNS) glia. While the etiologic mechanisms and the glial subtypes involved remain unresolved, infection of NG2 glia was recently observed to correlate spatially and temporally with altered neuronal physiology and spongiogenesis. Since one role of NG2 cells is to serve as oligodendrocyte (OL) progenitor cells (OPCs), we examined here whether their infection by neurovirulent (FrCasE) or nonneurovirulent (Fr57E) ecotropic MLVs influenced their viability and/or differentiation. Here, we demonstrate that OPCs, but not OLs, are major CNS targets of both FrCasE and Fr57E. We also show that MLV infection of neural progenitor cells (NPCs) in culture did not affect survival, proliferation, or OPC progenitor marker expression but suppressed certain glial differentiation markers. Assessment of glial differentiation in vivo using transplanted transgenic NPCs showed that, while MLVs did not affect cellular engraftment or survival, they did inhibit OL differentiation, irrespective of MLV neurovirulence. In addition, in chimeric brains, where FrCasE-infected NPC transplants caused neurodegeneration, the transplanted NPCs proliferated. These results suggest that MLV infection is not directly cytotoxic to OPCs but rather acts to interfere with OL differentiation. Since both FrCasE and Fr57E viruses restrict OL differentiation but only FrCasE induces overt neurodegeneration, restriction of OL maturation alone cannot account for neuropathogenesis. Instead neurodegeneration may involve a two-hit scenario where interference with OPC differentiation combined with glial Env-induced neuronal hyperexcitability precipitates disease.
A variety of human and animal retroviruses are capable of causing central nervous system (CNS) neurodegeneration manifested as motor and cognitive deficits. These retroviruses infect a variety of CNS cell types; however, the specific role each cell type plays in neuropathogenesis remains to be established. The NG2 glia, whose CNS functions are only now emerging, are a newly appreciated viral target in murine leukemia virus (MLV)-induced neurodegeneration. Since one role of NG2 glia is that of oligodendrocyte progenitor cells (OPCs), we investigated here whether their infection by the neurovirulent MLV FrCasE contributed to neurodegeneration by affecting OPC viability and/or development. Our results show that both neurovirulent and nonneurovirulent MLVs interfere with oligodendrocyte differentiation. Thus, NG2 glial infection could contribute to neurodegeneration by preventing myelin formation and/or repair and by suspending OPCs in a state of persistent susceptibility to excitotoxic insult mediated by neurovirulent virus effects on other glial subtypes.
某些鼠白血病病毒（MLV）能够在小鼠中诱发致命的进行性海绵状运动神经元疾病，该疾病在很大程度上由中枢神经系统（CNS）神经胶质细胞内的病毒Env糖蛋白表达介导。虽然病因机制和涉及的神经胶质细胞亚型仍未明确，但最近观察到NG2神经胶质细胞感染在空间和时间上与神经元生理学改变和海绵状变性相关。由于NG2细胞的一个作用是作为少突胶质细胞（OL）祖细胞（OPC），我们在此研究了神经毒性（FrCasE）或非神经毒性（Fr57E）亲嗜性MLV对它们的感染是否会影响其活力和/或分化。在此，我们证明OPC而非OL是FrCasE和Fr57E的主要CNS靶标。我们还表明，培养的神经祖细胞（NPC）的MLV感染不影响存活、增殖或OPC祖细胞标志物表达，但抑制某些神经胶质分化标志物。使用移植的转基因NPC对体内神经胶质分化进行评估表明，虽然MLV不影响细胞植入或存活，但它们确实抑制OL分化，与MLV的神经毒性无关。此外，在嵌合脑中，FrCasE感染的NPC移植导致神经变性，移植的NPC会增殖。这些结果表明，MLV感染对OPC并非直接具有细胞毒性，而是通过干扰OL分化起作用。由于FrCasE和Fr57E病毒均限制OL分化，但只有FrCasE诱导明显的神经变性，因此仅OL成熟受限不能解释神经发病机制。相反，神经变性可能涉及一种双打击情况，即OPC分化受到干扰，再加上神经胶质Env诱导的神经元过度兴奋，从而引发疾病。
多种人类和动物逆转录病毒能够导致中枢神经系统（CNS）神经变性，表现为运动和认知缺陷。这些逆转录病毒感染多种CNS细胞类型；然而，每种细胞类型在神经发病机制中所起的具体作用仍有待确定。NG2神经胶质细胞的CNS功能刚刚开始显现，它是鼠白血病病毒（MLV）诱导的神经变性中新近认识到的病毒靶标。由于NG2神经胶质细胞的一个作用是作为少突胶质细胞祖细胞（OPC），我们在此研究了神经毒性MLV FrCasE对它们的感染是否通过影响OPC活力和/或发育而导致神经变性。我们的结果表明，神经毒性和非神经毒性MLV均会干扰少突胶质细胞分化。因此，NG2神经胶质细胞感染可能通过阻止髓鞘形成和/或修复以及使OPC处于对神经毒性病毒对其他神经胶质细胞亚型的作用所介导的兴奋性毒性损伤持续敏感的状态而导致神经变性。
