Abstract
Human cytomegalovirus (HCMV) infection is one of the leading prenatal causes of congenital mental retardation and deformities world-wide. Access to cultured human neuronal lineages, necessary to understand the species specific pathogenic effects of HCMV, has been limited by difficulties in sustaining primary human neuronal cultures. Human induced pluripotent stem (iPS) cells now provide an opportunity for such research. We derived iPS cells from human adult fibroblasts and induced neural lineages to investigate their susceptibility to infection with HCMV strain Ad169. Analysis of iPS cells, iPS-derived neural stem cells (NSCs), neural progenitor cells (NPCs) and neurons suggests that (i) iPS cells are not permissive to HCMV infection, i.e., they do not permit a full viral replication cycle; (ii) Neural stem cells have impaired differentiation when infected by HCMV; (iii) NPCs are fully permissive for HCMV infection; altered expression of genes related to neural metabolism or neuronal differentiation is also observed; (iv) most iPS-derived neurons are not permissive to HCMV infection; and (v) infected neurons have impaired calcium influx in response to glutamate.
Highlights
Human cytomegalovirus (HCMV), a member of the alpha herpes viridae family, is a major cause of neurological deficits in newborns
We report an induced pluripotent stem cell-based cellular model to investigate the effect of HCMV
We found that during the first 24 hours p.i., the viral infection changed the expression of 55 genes; 30 were up-regulated and 25 were downregulated (p,0.05, uncorrected, fold changes less than 0.8 or greater than 1.2, see Table 1). 14 out of 55 dysregulated genes were related to neuronal metabolism or neuronal differentiation (TH transcript variant 2, TH transcript variant 3, PNMA3, GAD1, BHLHE22, KCNQ2, GRIN1, septin 4, NRXN2, BEX5, OTP, SEMA3A, ABLIM1, PRNP, and APP) (Table 1)
Summary
Human cytomegalovirus (HCMV), a member of the alpha herpes viridae family, is a major cause of neurological deficits in newborns. Many investigators have used rodent cells to study the relative susceptibility of different neural lineages to mouse cytomegalovirus (MCMV) infection [2], [3]. Stage mouse embryos are not permissive for MCMV infection; i.e., even if HCMV enters the host cell, it is unable to complete replication cycles [4]. Mouse embryonic stem (ES) cells are refractory to MCMV infection. Whether mouse neurons are refractory to infection is controversial [2]. The inconsistent results may reflect difficulties in obtaining pure neuronal cells devoid of glial cells, which are known to be permissive to MCMV [2]. Damage to neurons observed in mixed cultures in some studies may reflect events secondary to glial infection and death [2]
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