Human cytomegalovirus infection causes premature and abnormal differentiation of human neural progenitor cells.
Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, largely manifested as central nervous system (CNS) disorders. The principal site of manifestations in the mouse model is the fetal brain's neural progenitor cell (NPC)-rich subventricular zone. Our previous human NPC studies found these cells to be fully permissive for HCMV and a useful in vitro model system. In continuing work, we observed that under culture conditions favoring maintenance of multipotency, infection caused NPCs to quickly and abnormally differentiate. This phenotypic change required active viral transcription. Whole-genome expression analysis found rapid downregulation of genes that maintain multipotency and establish NPCs' neural identity. Quantitative PCR, Western blot, and immunofluorescence assays confirmed that the mRNA and protein levels of four hallmark NPC proteins (nestin, doublecortin, sex-determining homeobox 2, and glial fibrillary acidic protein) were decreased by HCMV infection. The decreases required active viral replication and were due, at least in part, to proteasomal degradation. Our results suggest that HCMV infection causes in utero CNS defects by inducing both premature and abnormal differentiation of NPCs.
Luo
Min Hua
MH
Department of Microbiology, Molecular Biology and Biochemistry, University of Idaho, Moscow, ID 83844-3052, USA.
Hannemann
Holger
H
Kulkarni
Amit S
AS
Schwartz
Philip H
PH
O'Dowd
John M
JM
Fortunato
Elizabeth A
EA
D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D003586:Cytomegalovirus Infections / Q000473:pathology*; D015536:Down-Regulation; D015774:Ganciclovir / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D009474:Neurons / Q000473:pathology*; D061988:Proteasome Inhibitors; D013234:Stem Cells / Q000473:pathology*; D014779:Virus Replication
D061988:Proteasome Inhibitors; D015774:Ganciclovir