Downregulation of the epidermal growth factor receptor by human cytomegalovirus infection in human fetal lung fibroblasts.
Epidermal growth factor plays a key role in late fetal lung development and differentiation as well as in regulating surfactant protein A synthesis, which is involved in innate immunity of the lung. Here we show that human cytomegalovirus (HCMV), a known lung pathogen in connatal and postnatal infection of neonates as well as transplant recipients, completely down-regulates EGF receptor (EGF-R) on the surface of human fetal lung fibroblasts. Inhibition of EGF-R synthesis occurs on the transcriptional rather than on the posttranscriptional level. The effect essentially depends on expression of viral immediate early and/or early genes, as binding of ultraviolet light-inactivated virus to the cells had no effect on EGF-R expression. Furthermore, the anti-HCMV drug ganciclovir, which blocks HCMV DNA replication and late gene expression, cannot overcome HCMV-mediated inhibition of EGF-R, suggesting that immediate early or early gene products may be responsible for down-regulation of EGF-R. Interestingly, the glucocorticoid dexamethasone, which is used for its antiinflammatory action to prevent chronic lung disease in preterm infants, promotes HCMV-associated downregulation of the EGF-R by stimulation of viral gene expression. From these data it can be hypothesized that the pathogenesis of HCMV lung infection involves down-regulation of EGF-R and that congenital HCMV infection may cause retardation in lung maturation and surfactant protein synthesis.
Beutler
Thomas
T
Institute of Virology and Department of Neonatology, University Hospital Charité, Humboldt University, Berlin, Germany.
Höflich
Conny
C
Stevens
Paul A
PA
Krüger
Detlev H
DH
Prösch
Susanna
S
D000998:Antiviral Agents / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D015774:Ganciclovir / Q000494:pharmacology; D015870:Gene Expression; D017781:Genes, Immediate-Early; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics
D000998:Antiviral Agents; D012333:RNA, Messenger; D003907:Dexamethasone; D066246:ErbB Receptors; D015774:Ganciclovir