PMID- 30971470 OWN - NLM STAT- MEDLINE DCOM- 20200528 LR - 20231114 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 93 IP - 13 DP - 2019 Jul 1 TI - Antagonizing the Glucocorticoid Receptor Impairs Explant-Induced Reactivation in Mice Latently Infected with Herpes Simplex Virus 1. LID - 10.1128/JVI.00418-19 [doi] LID - e00418-19 AB - Herpes simplex virus 1 (HSV-1) establishes lifelong latent infections in neurons. Reactivation from latency can lead to serious recurrent disease, including stromal keratitis, corneal scarring, blindness, and encephalitis. Although numerous studies link stress to an increase in the incidence of reactivation from latency and recurrent disease, the mechanism of action is not well understood. We hypothesized that stress, via corticosteroid-mediated activation of the glucocorticoid receptor (GR), stimulates viral gene expression and productive infection during reactivation from latency. Consequently, we tested whether GR activation by the synthetic corticosteroid dexamethasone influenced virus shedding during reactivation from latency using trigeminal ganglion (TG) explants from Swiss Webster mice latently infected with HSV-1, strain McKrae. TG explants from the latently infected mice shed significantly higher levels of virus when treated with dexamethasone. Conversely, virus shedding from TG explants was significantly impaired when they were incubated with medium containing a GR-specific antagonist (CORT-108297) or stripped fetal bovine serum, which lacks nuclear hormones and other growth factors. TG explants from latently infected, but not uninfected, TG contained significantly more GR-positive neurons following explant when treated with dexamethasone. Strikingly, VP16 protein expression was detected in TG neurons at 8 hours after explant whereas infected-cell protein 0 (ICP0) and ICP4 protein expression was not readily detected until 16 hours after explant. Expression of all three viral regulatory proteins was stimulated by dexamethasone. These studies indicated corticosteroid-mediated GR activation increased the number of TG neurons expressing viral regulatory proteins, which enhanced virus shedding during explant-induced reactivation from latency.IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes lifelong latent infections in neurons within trigeminal ganglia (TG); periodically, reactivation from latency occurs, leading to virus transmission and recurrent disease. Chronic or acute stress increases the frequency of reactivation from latency; how this occurs is not well understood. Here, we demonstrate that the synthetic corticosteroid dexamethasone stimulated explant-induced reactivation from latency. Conversely, a glucocorticoid receptor (GR) antagonist significantly impaired reactivation from latency, indicating that GR activation stimulated explant-induced reactivation. The viral regulatory protein VP16 was readily detected in TG neurons prior to infected-cell protein 0 (ICP0) and ICP4 during explant-induced reactivation. Dexamethasone induced expression of all three viral regulatory proteins following TG explant. Whereas the immunosuppressive properties of corticosteroids would facilitate viral spread during reactivation from latency, these studies indicate GR activation increases the number of TG neurons that express viral regulatory proteins during early stages of explant-induced reactivation. CI - Copyright (c) 2019 American Society for Microbiology. FAU - Harrison, Kelly S AU - Harrison KS AD - Oklahoma State University Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA. FAU - Zhu, Liqian AU - Zhu L AD - Oklahoma State University Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA. AD - Yangzhou University, College of Veterinary Medicine and Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou, China. FAU - Thunuguntla, Prasanth AU - Thunuguntla P AD - Oklahoma State University Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA. FAU - Jones, Clinton AU - Jones C AD - Oklahoma State University Center for Veterinary Health Sciences, Department of Veterinary Pathobiology, Stillwater, Oklahoma, USA clint.jones10@okstate.edu. LA - eng GR - P20 GM103648/GM/NIGMS NIH HHS/United States GR - R01 NS111167/NS/NINDS NIH HHS/United States GR - R21 NS102290/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20190614 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Herpes Simplex Virus Protein Vmw65) RN - 0 (Immediate-Early Proteins) RN - 0 (Receptors, Glucocorticoid) RN - 0 (Viral Proteins) RN - 0 (herpes simplex virus, type 1 protein ICP4) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.3.2.27 (Vmw110 protein, Human herpesvirus 1) SB - IM MH - Animals MH - Disease Models, Animal MH - Female MH - Gene Expression Regulation, Viral MH - Herpes Simplex Virus Protein Vmw65/metabolism MH - Herpesvirus 1, Human/genetics/*physiology MH - Immediate-Early Proteins/metabolism MH - Mice MH - Neurons/virology MH - Receptors, Glucocorticoid/*antagonists & inhibitors/*metabolism MH - Stress, Physiological MH - Trigeminal Ganglion/pathology/virology MH - Ubiquitin-Protein Ligases/metabolism MH - Viral Proteins/genetics/metabolism MH - Virus Activation/genetics/physiology MH - Virus Latency/*drug effects/genetics/*physiology MH - Virus Shedding PMC - PMC6580953 OTO - NOTNLM OT - HSV-1 OT - reactivate OT - stress response EDAT- 2019/04/12 06:00 MHDA- 2020/05/29 06:00 PMCR- 2019/12/14 CRDT- 2019/04/12 06:00 PHST- 2019/03/09 00:00 [received] PHST- 2019/03/29 00:00 [accepted] PHST- 2019/04/12 06:00 [pubmed] PHST- 2020/05/29 06:00 [medline] PHST- 2019/04/12 06:00 [entrez] PHST- 2019/12/14 00:00 [pmc-release] AID - JVI.00418-19 [pii] AID - 00418-19 [pii] AID - 10.1128/JVI.00418-19 [doi] PST - epublish SO - J Virol. 2019 Jun 14;93(13):e00418-19. doi: 10.1128/JVI.00418-19. Print 2019 Jul 1.