Ovanesov Mikhail V, Sauder Christian, Rubin Steven A, Richt Jürgen, Nath Avindra, Carbone Kathryn M, Pletnikov Mikhail V
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, CMSC 8-121, Baltimore, MD 21287, USA.
J Virol. 2006 Dec;80(24):12141-8. doi: 10.1128/JVI.01648-06. Epub 2006 Oct 4.
Neonatal Borna disease virus (BDV) infection of the rat brain is associated with microglial activation and damage to the certain neuronal populations. Since persistent BDV infection of neurons in vitro is noncytolytic and noncytopathic, activated microglia have been suggested to be responsible for neuronal cell death in vivo. However, the mechanisms of activation of microglia in neonatally BDV-infected rat brain have not been investigated. To address these issues, activation of primary rat microglial cells was studied following exposure to purified BDV or to persistently BDV-infected primary cortical neurons or after BDV infection of primary mixed neuron-glial cultures. Neither purified virus nor BDV-infected neurons alone activated primary microglia as assessed by the changes in cell shape or production of the proinflammatory cytokines. In contrast, in the BDV-infected primary mixed cultures, we observed proliferation of microglia cells that acquired the round morphology and expressed major histocompatibility complex molecules of classes I and II. These manifestations of microglia activation were observed in the absence of direct BDV infection of microglia or overt neuronal toxicity. In addition, compared to uninfected mixed cultures, activation of microglia in BDV-infected mixed cultures was associated with a significantly greater lipopolysaccharide-induced release of tumor necrosis factor alpha, interleukin 1beta, and interleukin 10. Taken together, the present data are the first in vitro evidence that persistent BDV infection of neurons and astrocytes rather than direct exposure to the virus or dying neurons is critical for activating microglia.
新生大鼠脑部的博尔纳病病毒（BDV）感染与小胶质细胞激活以及特定神经元群体的损伤有关。由于体外神经元的持续性BDV感染是非溶细胞性和非细胞病变性的，因此有人提出激活的小胶质细胞是体内神经元细胞死亡的原因。然而，新生BDV感染大鼠脑中的小胶质细胞激活机制尚未得到研究。为了解决这些问题，我们研究了原代大鼠小胶质细胞在暴露于纯化的BDV、持续性BDV感染的原代皮质神经元后或原代混合神经元-胶质细胞培养物BDV感染后的激活情况。通过细胞形态变化或促炎细胞因子的产生评估，纯化病毒和单独的BDV感染神经元均未激活原代小胶质细胞。相反，在BDV感染的原代混合培养物中，我们观察到小胶质细胞增殖，这些细胞呈现圆形形态并表达I类和II类主要组织相容性复合体分子。在没有小胶质细胞直接BDV感染或明显神经元毒性的情况下观察到了这些小胶质细胞激活的表现。此外，与未感染的混合培养物相比，BDV感染的混合培养物中小胶质细胞的激活与脂多糖诱导的肿瘤坏死因子α、白细胞介素1β和白细胞介素10释放显著增加有关。综上所述，目前的数据是首个体外证据，表明神经元和星形胶质细胞的持续性BDV感染而非直接接触病毒或濒死神经元对于激活小胶质细胞至关重要。
