Anderson G W, Palmer G A, Rowland R R, Even C, Plagemann P G
Department of Microbiology, Medical School, University of Minnesota, Minneapolis 55455-0312.
J Virol. 1995 Jan;69(1):308-19. doi: 10.1128/JVI.69.1.308-319.1995.
Certain mouse strains, such as AKR and C58, which possess N-tropic, ecotropic murine leukemia virus (MuLV) proviruses and are homozygous at the Fv-1n locus are specifically susceptible to paralytic infection (age-dependent poliomyelitis [ADPM]) by lactate dehydrogenase-elevating virus (LDV). Our results provide an explanation for this genetic linkage and directly prove that ecotropic MuLV infection of spinal cord cells is responsible for rendering anterior horn neurons susceptible to cytocidal LDV infection, which is the cause of the paralytic disease. Northern (RNA) blot hybridization of total tissue RNA and in situ hybridization of tissue sections demonstrated that only mice harboring central nervous system (CNS) cells that expressed ecotropic MuLV were susceptible to ADPM. Our evidence indicates that the ecotropic MuLV RNA is transcribed in CNS cells from ecotropic MuLV proviruses that have been acquired by infection with exogenous ecotropic MuLV, probably during embryogenesis, the time when germ line proviruses in AKR and C58 mice first become activated. In young mice, MuLV RNA-containing cells were found exclusively in white-matter tracts and therefore were glial cells. An increase in the ADPM susceptibility of the mice with advancing age correlated with the presence of an increased number of ecotropic MuLV RNA-containing cells in the spinal cords which, in turn, correlated with an increase in the number of unmethylated proviruses in the DNA extracted from spinal cords. Studies with AKXD recombinant inbred strains showed that possession of a single replication-competent ecotropic MuLV provirus (emv-11) by Fv-1n/n mice was sufficient to result in ecotropic MuLV infection of CNS cells and ADPM susceptibility. In contrast, no ecotropic MuLV RNA-positive cells were present in the CNSs of mice carrying defective ecotropic MuLV proviruses (emv-3 or emv-13) or in which ecotropic MuLV replication was blocked by the Fv-1n/b or Fv-1b/b phenotype. Such mice were resistant to paralytic LDV infection. In utero infection of CE/J mice, which are devoid of any endogenous ecotropic MuLVs, with the infectious clone of emv-11 (AKR-623) resulted in the infection of CNS cells, and the mice became ADPM susceptible, whereas littermates that had not become infected with ecotropic MuLV remained ADPM resistant.
某些小鼠品系，如AKR和C58，它们携带N-嗜性、亲嗜性鼠白血病病毒（MuLV）前病毒，并且在Fv-1n位点是纯合子，对乳酸脱氢酶升高病毒（LDV）引起的麻痹性感染（年龄依赖性脊髓灰质炎[ADPM]）具有特异性易感性。我们的结果为这种基因连锁提供了解释，并直接证明脊髓细胞的亲嗜性MuLV感染导致前角神经元易受杀细胞性LDV感染，而这正是麻痹性疾病的病因。对总组织RNA进行Northern（RNA）印迹杂交以及对组织切片进行原位杂交表明，只有那些中枢神经系统（CNS）细胞表达亲嗜性MuLV的小鼠才易患ADPM。我们的证据表明，亲嗜性MuLV RNA是在CNS细胞中由亲嗜性MuLV前病毒转录而来，这些前病毒可能是在胚胎发育期间，即AKR和C58小鼠种系前病毒首次被激活时，通过感染外源性亲嗜性MuLV而获得的。在幼鼠中，含有MuLV RNA的细胞仅在白质束中被发现，因此是神经胶质细胞。随着年龄增长，小鼠对ADPM的易感性增加与脊髓中含亲嗜性MuLV RNA细胞数量的增加相关，而这又与从脊髓中提取的DNA中未甲基化前病毒数量的增加相关。对AKXD重组近交系的研究表明，Fv-1n/n小鼠拥有单个具有复制能力的确亲嗜性MuLV前病毒（emv-11）就足以导致CNS细胞发生亲嗜性MuLV感染并使其易患ADPM。相比之下，携带缺陷亲嗜性MuLV前病毒（emv-3或emv-13）的小鼠或亲嗜性MuLV复制被Fv-1n/b或Fv-1b/b表型阻断的小鼠的中枢神经系统中不存在亲嗜性MuLV RNA阳性细胞。这些小鼠对麻痹性LDV感染具有抗性。对不含任何内源性亲嗜性MuLV的CE/J小鼠进行子宫内感染emv-11（AKR-623）的感染性克隆，导致CNS细胞被感染，这些小鼠变得易患ADPM，而未感染亲嗜性MuLV的同窝小鼠仍然对ADPM具有抗性。
