The Glucocorticoid Receptor (GR) Stimulates Herpes Simplex Virus 1 Productive Infection, in Part Because the Infected Cell Protein 0 (ICP0) Promoter Is Cooperatively Transactivated by the GR and Krüppel-Like Transcription Factor 15

Abstract

Following acute infection, herpes simplex virus 1 (HSV-1) establishes lifelong latency in neurons. Physical, emotional, and chemical stresses are linked to increasing the incidence of reactivation from latency, but the mechanism of action is not well understood. In general, stress increases corticosteroid levels, leading to activation of the glucocorticoid receptor (GR), a pioneer transcription factor. Consequently, we hypothesized that stress-mediated activation of the GR can stimulate productive infection and viral gene expression. New studies demonstrated that the GR-specific antagonist (CORT-108297) significantly reduced HSV-1 productive infection in mouse neuroblastoma cells (Neuro-2A). Additional studies demonstrated that the activated GR and Krüppel-like transcription factor 15 (KLF15) cooperatively transactivated the infected cell protein 0 (ICP0) promoter, a crucial viral regulatory protein. Interestingly, the synthetic corticosteroid dexamethasone and GR or KLF15 alone had little effect on ICP0 promoter activity in transfected Neuro-2A or Vero cells. Chromatin immunoprecipitation (ChIP) studies revealed that the GR and KLF15 occupied ICP0 promoter sequences important for transactivation at 2 and 4 h after infection; however, binding was not readily detected at 6 h after infection. Similar results were obtained for cells transfected with the full-length ICP0 promoter. ICP0 promoter sequences lack a consensus “whole” GR response element (GRE) but contain putative half-GREs that were important for dexamethasone induced promoter activity. The activated GR stimulates expression of, and interacts with, KLF15; consequently, these data suggest KLF15 and the GR form a feed-forward loop that activates viral gene expression and productive infection following stressful stimuli. IMPORTANCE The ability of herpes simplex virus 1 (HSV-1) to periodically reactivate from latency results in virus transmission and recurrent disease. The incidence of reactivation from latency is increased by chronic or acute stress. Stress increases the levels of corticosteroids, which bind and activate the glucocorticoid receptor (GR). Since GR activation is an immediate early response to stress, we tested whether the GR influences productive infection and the promoter that drives infected cell protein 0 (ICP0) expression. Pretreatment of cells with a GR-specific antagonist (CORT-108297) significantly reduced virus replication. Although the GR had little effect on ICP0 promoter activity alone, the Krüppel-like transcription factor 15 (KLF15) cooperated with the GR to stimulate promoter activity in transfected cells. In transfected or infected cells, the GR and KLF15 occupied ICP0 sequences important for transactivation. Collectively, these studies provide insight into how stress can directly stimulate productive infection and viral gene expression.

Antagonizing the Glucocorticoid Receptor Impairs Explant-Induced Reactivation in Mice Latently Infected with Herpes Simplex Virus 1

“…The results of this study demonstrated that explant-induced reactivation from latency was stimulated by the synthetic corticosteroid DEX but was significantly reduced by a GR-specific antagonist (CORT-108297). CORT-108297 also significantly reduced viral replication in cultured cells (65), consistent with TG explant findings. Previous studies reported DEX accelerated explant-induced reactivation (21,22); however, these studies may have underestimated the effects of adding DEX to TG explants, because FBS was used in the studies.…”

“…A VP16 coactivator, host cell factor 1 (HCF-1), also localizes to the nucleus during explant-induced reactivation from latency (88), suggesting VP16 can transactivate IE gene expression during early stages of reactivation. Although the proximal VP16, ICP0, and ICP4 promoters do not contain consensus "whole" GREs, the ICP0 promoter is cooperatively transactivated by GR, DEX, and Krüppel-like transcription factor 15 (65). A 1 ⁄2 GRE in ICP0 promoter sequences was important for DEX-induced transcription mediated by GR and KLF15, suggesting multiple stress-induced factors are important for activating viral gene expression during early stages of reactivation.…”

“…ADV509447843) reconstituted in DMSO was added to the TG explants. Each day, 100 l medium was removed and used to perform plaque assays on Vero cell monolayers as previously described (65).…”

Consensus transcriptional regulatory networks of coronavirus-infected human cells

“…Receptors Reflecting their well-documented roles in the response to CoV infection 18-21 , we observed appreciable significant intersections between CoV HCTs and those of the [22][23][24][25][26] . The Notch 9 receptor HCT intersection points to a possible mechanistic basis for the potential of Notch pathway modulation in the treatment of SARS2 27 .…”

Autophagic degradation of PML promotes susceptibility to HSV-1 by stress-induced Corticosterone

“…It has been revealed that stress increases corticosteroid levels, leading to activation of the glucocorticoid receptor (GR). The activated GR stimulates HSV-1 productive infection, in part because the ICP0 promoter is cooperatively transactivated by the GR and Krüppel-like transcription factor 15 (KLF15) 8 .…”