Nagra R M, Burrola P G, Wiley C A
Department of Pathology, School of Medicine, University of California, San-Diego, La Jolla.
Lab Invest. 1992 Mar;66(3):292-302.
The Cas-Br-E strain of murine leukemia virus is a neurovirulent retrovirus that induces progressive noninflammatory degeneration of the central nervous system (CNS). The molecular clone pNE-8 retains pathogenic properties of Cas-Br-E. The neurotropic determinants are known; however, the mechanism of neuropathogenesis is unknown. We examined the temporal development of disease after infection of SWR/J mice with pNE-8 virus. Development of CNS lesions, cellular targets of viral replication, accumulation of ubiquitinated proteins and integrity of blood-brain barrier were determined in mice infected with pNE-8 virus; and compared with uninfected, sham-infected, and nonneuropathogenic virus-infected mice. During 24 weeks of pNE-8 infection, noninflammatory spongiform lesions developed initially in the lumbar spinal cord and progressed to involve the brainstem and deep cerebellar nuclei. Virions and viral antigens accumulated for 18 weeks postinfection and then declined. Major sites of viral infection outside the CNS were splenic megakaryocytes, and skeletal muscle. Cellular targets of viral replication in the CNS included neurons, oligodendrocytes, and capillary endothelium. No astrocytic infection was observed; however, a reactive gliosis marked the development of clinical symptoms and histopathology. Spongiform lesions began as swelling of perivascular astrocytic processes. Intramyelinic vacuoles with splitting of myelin at major dense lines were prominent around dystrophic axons at later time points. Dendritic processes showed vacuolization and local degeneration. Viral particles were most commonly observed in extracellular spaces and within rough endoplasmic reticulum of neurons, oligodendrocytes, and splenic megakaryocytes. Infected megakaryocytes and regions of spleen containing viral aggregates showed accumulation of ubiquitinated proteins. Areas of histopathology in the CNS showed accumulation of ubiquitinated proteins but unlike spleen, viral proteins were not highly ubiquitinated. Disruption of the blood brain barrier was only evident at late stages of infection. In conclusion, the neuropathogenic damage associated with pNE-8 infection appears to be tightly associated with direct viral infection of oligodendroglia and neurons.
小鼠白血病病毒的Cas-Br-E株是一种神经毒性逆转录病毒，可诱发中枢神经系统（CNS）进行性非炎性变性。分子克隆pNE-8保留了Cas-Br-E的致病特性。嗜神经决定因素已知，但神经发病机制尚不清楚。我们研究了用pNE-8病毒感染SWR/J小鼠后疾病的时间发展过程。在感染pNE-8病毒的小鼠中确定了CNS病变的发展、病毒复制的细胞靶点、泛素化蛋白的积累以及血脑屏障的完整性；并与未感染、假感染和非神经致病病毒感染的小鼠进行比较。在pNE-8感染的24周内，非炎性海绵状病变最初在腰脊髓出现，并进展至累及脑干和小脑深部核团。感染后18周，病毒粒子和病毒抗原积累，然后下降。CNS外的主要病毒感染部位是脾巨核细胞和骨骼肌。CNS中病毒复制的细胞靶点包括神经元、少突胶质细胞和毛细血管内皮细胞。未观察到星形胶质细胞感染；然而，反应性胶质增生标志着临床症状和组织病理学的发展。海绵状病变开始于血管周围星形胶质细胞突起的肿胀。在后期，营养不良轴突周围的髓鞘内空泡和主要致密线处的髓鞘分裂很明显。树突状突起显示空泡化和局部变性。病毒颗粒最常见于细胞外空间以及神经元、少突胶质细胞和脾巨核细胞的粗面内质网内。感染的巨核细胞和含有病毒聚集体的脾区域显示泛素化蛋白的积累。CNS中的组织病理学区域显示泛素化蛋白的积累，但与脾脏不同，病毒蛋白没有高度泛素化。血脑屏障的破坏仅在感染后期明显。总之，与pNE-8感染相关的神经致病损伤似乎与少突胶质细胞和神经元的直接病毒感染密切相关。
