Cyclosporine inhibits mouse cytomegalovirus infection via a cyclophilin-dependent pathway specifically in neural stem/progenitor cells
Cyclosporine inhibits mouse cytomegalovirus infection via a cyclophilin-dependent pathway specifically in neural stem/progenitor cells
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DOI：
10.1128/jvi.00261-07
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发表时间：
2007-09-01
影响因子：
5.4
通讯作者：
Tsutsui, Yoshihiro
中科院分区：
文献类型：
--
作者：
Kawasaki, Hideya;Mocarski, Edward S.;Tsutsui, Yoshihiro
神经干细胞和祖细胞（NSPC）移植在神经退行性疾病中的潜力引起了对免疫抑制剂和可能干扰植入的机会性嗜神经病原体的关注。巨细胞病毒（CMV）是一种重要的机会致病菌，感染中枢神经系统，在那里它可以保持潜伏的生活，经胎盘传播。环孢菌素（Cs）是一种用于器官移植的免疫抑制药物，其使用与CMV再激活有关，可抑制培养的NSPCs中的鼠CMV（MCMV）感染，但不抑制成纤维细胞中的感染。Cs的这种活性似乎是通过亲环蛋白（CyP）介导的，而不是通过钙调神经磷酸酶。首先，钙调神经磷酸酶特异性抑制剂FK 506未能抑制复制。第二，CyP特异性抑制剂NIM811强烈抑制NSPC中的复制。在NIM811存在下维持的NSPCs保留病毒基因组数周，而没有可检测的病毒基因表达或明显的有害作用。NIM811的撤销重新激活病毒复制，表明抑制机制是可逆的。最后，通过小干扰RNA抑制内源性CyPA（CyPA）也抑制NSPCs中的复制。这些结果表明，MCMV复制依赖于NSPC中的细胞CyPA途径（以特定的细胞类型依赖性方式），CyPA在该细胞类型中的病毒感染中起重要作用，并且通过CyP抑制病毒复制导致病毒基因组的持续存在而不损伤细胞。此外，在T细胞中赋予免疫抑制的钙调神经磷酸酶信号传导途径不会以可检测的方式影响病毒复制。
The potential of neural stem and progenitor cell (NSPC) transplantation in neurodegenerative disease raises a concern about immunosuppressive agents and opportunistic neurotropic pathogens that may interfere with engraftment. Cytomegalovirus (CMV) is an important opportunistic pathogen infecting the central nervous system, where it may remain latent for life, following transplacental transmission. Cyclosporine (Cs), an immunosuppressive drug used in organ transplantation, where its use is associated with CMV reactivation, suppressed murine CMV (MCMV) infection in cultured NSPCs but not in fibroblasts. This activity of Cs appears to be mediated via cyclophilin (CyP) rather than via calcineurin. First, the calcineurin-specific inhibitor FK506 failed to suppress replication. Second, the CyP-specific inhibitor NIM811 strongly suppressed replication in NSPC. NSPCs maintained in the presence of NIM811 retained viral genomes for several weeks without detectable viral gene expression or obvious deleterious effects. The withdrawal of NIM811 reactivated viral replication, suggesting that the inhibitory mechanism was reversible. Finally, inhibition of endogenous CyP A (CyPA) by small interfering RNA also inhibited replication in NSPCs. These results show that MCMV replication depends upon cellular CyPA pathways in NSPCs (in a specific cell type-dependent fashion), that CyPA plays an important role in viral infection in this cell type, and that inhibition of viral replication via CyP leads to persistence of the viral genome without cell damage. Further, the calcineurin-signaling pathway conferring immunosuppression in T cells does not influence viral replication in a detectable fashion.