Glucocorticoids activate Epstein Barr virus lytic replication through the upregulation of immediate early BZLF1 gene expression.
Psychological stress-associated immune dysregulation has been shown to disrupt the steady-state expression and reactivate latent herpes viruses. One such virus is the Epstein Barr virus (EBV), which is associated with several human malignancies. EBV infects >90% of people living in North America and persists for life in latently infected cells. Although several studies have shown that glucocorticoids (GCs) can directly induce reactivation of the latent virus, the mechanism of stress hormone involvement in the control of EBV gene expression is not well understood. In this study, we tested the hypothesis that GCs can induce the latent EBV genome to lytically replicate through the induction of the EBV immediate early gene BZLF1 which encodes the lytic transactivator protein ZEBRA. We show a dose-dependent upregulation of BZLF1 mRNA expression by hydrocortisone (HC) and dexamethasone (Dex) in Daudi cells, an EBV genome positive Burkitt's lymphoma cell line, and Dex-induction of the early gene products BLLF3 (encoding for the EBV dUTPase) and BALF5 (encoding for the EBV DNA polymerase). We show that Daudi cells express glucocorticoid receptors (GR) that mediate Dex-dependent upregulation of BZLF1 mRNA levels. This effect was inhibited by both the glucocorticoid receptor antagonist RU486 and by cycloheximide. The results suggest that GCs, in addition to inducing stress-related immune dysregulation, can mediate latent EBV reactivation through the induction of the BZLF1 gene.
Yang
Eric V
EV
Institute for Behavioral Medicine Research, The Ohio State University Medical Center, 460 Medical Center Drive, Columbus, OH 43210, USA.
Webster Marketon
Jeanette I
JI
Chen
Min
M
Lo
Kwok Wai
KW
Kim
Seung-jae
SJ
Glaser
Ronald
R
D015153:Blotting, Western; D002051:Burkitt Lymphoma; D002460:Cell Line; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000378:metabolism; D017781:Genes, Immediate-Early / Q000187:drug effects / Q000235:genetics*; D005938:Glucocorticoids / Q000494:pharmacology*; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011755:Pyrophosphatases / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
C063676:BZLF1 protein, Herpesvirus 4, Human; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D006727:Hormone Antagonists; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D014764:Viral Proteins; D015735:Mifepristone; D003907:Dexamethasone; D003513:Cycloheximide; C083202:BALF5 protein, Epstein-barr virus; D004259:DNA-Directed DNA Polymerase; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase
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