Lynch W P, Robertson S J, Portis J L
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infections Diseases, Hamilton, Montana 59840.
J Virol. 1995 Mar;69(3):1408-19. doi: 10.1128/JVI.69.3.1408-1419.1995.
FrCasE is a highly neurovirulent murine leukemia virus which causes a noninflammatory spongiform neurodegenerative disease after neonatal inoculation. The central nervous system (CNS) infection is wide-spread, involving several different cell types, whereas the lesions are localized to motor areas of the brain and spinal cord. Inoculation of FrCasE at 10 days of age (P10) results in viremia, but infection of the CNS is restricted and neurological disease is not observed (M. Czub, S. Czub, F. McAtee, and J. Portis, J. Virol. 65:2539-2544, 1991). In this study, we used this developmental resistance to restrict the extent and the distribution of FrCasE in the brain to examine whether the spongiform degeneration is a consequence of infection of cells in proximity to the lesions. Two approaches were used to infect the brain on or after P10. First, mice were inoculated with FrCasE at P10 to induce viremia and then at P17 were subjected to focal CNS injury within brain regions known to be susceptible to virus-induced spongiform degeneration. The injury resulted in local inflammation, glial activation, migration of inflammatory cells into the wound site, and high-level parenchymal infection about the wound site. However, no evidence of spongiform neurodegeneration was observed over a period of 3 months. The second approach involved the implantation of FrCasE-infected microglia into the CNS at > or = P10. This resulted in microglial engraftment and focal CNS infection unilaterally at the implantation sites and bilaterally along white matter tracts of the corpus callosum and pons and in cells of the subventricular layers of the lateral cerebral ventricles. Strikingly, focal spongiform degeneration colocalized with the sites of infection. In contrast to the wounding experiments, the implantation model was not associated with an inflammatory response or significant glial activation. Results of these studies suggest that (i) the developmental resistance of the CNS to infection lies at the blood-brain barrier and can be bypassed by direct introduction into the brain of virus-infected cells, (ii) the neuropathology induced by this virus is a consequence of local effects of the infection and does not appear to require endothelial or neuronal infection, and (iii) elements of the inflammatory response and/or glial activation may modulate the expression of neuropathology induced by neurovirulent retroviruses.
FrCasE是一种具有高度神经毒性的鼠白血病病毒，新生小鼠接种后会引发一种非炎症性海绵状神经退行性疾病。中枢神经系统（CNS）感染广泛，涉及多种不同细胞类型，而病变局限于脑和脊髓的运动区域。在10日龄（P10）接种FrCasE会导致病毒血症，但CNS感染受到限制，未观察到神经疾病（M. Czub、S. Czub、F. McAtee和J. Portis，《病毒学杂志》65:2539 - 2544，1991）。在本研究中，我们利用这种发育抗性来限制FrCasE在脑中的范围和分布，以检查海绵状变性是否是病变附近细胞感染的结果。采用两种方法在P10及之后感染脑部。首先，在P10给小鼠接种FrCasE以诱导病毒血症，然后在P17对已知易受病毒诱导的海绵状变性影响的脑区域进行局灶性CNS损伤。该损伤导致局部炎症、胶质细胞活化、炎性细胞迁移至伤口部位以及伤口部位周围高水平的实质感染。然而，在3个月的时间内未观察到海绵状神经变性的证据。第二种方法涉及在≥P10时将感染FrCasE的小胶质细胞植入CNS。这导致小胶质细胞植入以及在植入部位单侧和沿胼胝体和脑桥白质束双侧以及侧脑室室管膜下层细胞中出现局灶性CNS感染。引人注目的是，局灶性海绵状变性与感染部位共定位。与创伤实验不同，植入模型与炎症反应或显著的胶质细胞活化无关。这些研究结果表明：（i）CNS对感染的发育抗性存在于血脑屏障，通过将病毒感染细胞直接引入脑内可绕过该屏障；（ii）这种病毒诱导的神经病理学是感染局部效应的结果，似乎不需要内皮细胞或神经元感染；（iii）炎症反应和/或胶质细胞活化的因素可能调节神经毒性逆转录病毒诱导的神经病理学表达。
