Cyclosporin A inhibits mouse cytomegalovirus infection via a cyclophilin-dependent pathway specifically in neural stem/progenitor cells

Authors:
Kawasaki H, Mocarski ES, Kosugi I, Tsutsui Y
In:
Source: J Virol
Publication Date: (2007)
Issue: 81(17): 9013-23
Research Area:
Neurobiology
Cells used in publication:
NIH/3T3
Species: mouse
Tissue Origin: embryo
Neural stem cell (NSC), mouse
Species: mouse
Tissue Origin: brain
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
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 following transplacental transmission where it may remain latent for life. Cyclosporin A (CsA), an immunosuppressive drug used in organ transplantation where its use is associated with CMV reactivation, suppressed murine CMV (MCMV) infection in cultured NSPC, but not in fibroblasts. This activity of CsA appears to be mediated via cyclophilin (CyP) rather than via calcineurin. First, the calicineurin-specific inhibitor FK506 failed to suppress replication. Second, the cyclophilin-specific inhibitor NIM811 strongly suppressed replication in NSPC. NSPC maintained in the presence of NIM811 retained viral genomes for several weeks without detectable viral gene expression or obvious deleterious effects. Withdrawal of NIM811 reactivated viral replication, suggesting that the inhibitory mechanism was reversable. Finally, inhibition of endogenous cyclophilin A (CyPA) by siRNA also inihibited replication in NSPC. These results show that MCMV replication depends upon cellular CyPA pathways in NSPC (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.