PMID- 38084958
OWN - NLM
STAT- MEDLINE
DCOM- 20240130
LR  - 20240517
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 98
IP  - 1
DP  - 2024 Jan 23
TI  - Specificity protein 1 (Sp1) and glucocorticoid receptor (GR) stimulate bovine 
      alphaherpesvirus 1 (BoHV-1) replication and cooperatively transactivate the 
      immediate early transcription unit 1 promoter.
PG  - e0143623
LID - 10.1128/jvi.01436-23 [doi]
LID - e01436-23
AB  - Bovine alphaherpesvirus 1 (BoHV-1) infections cause respiratory tract disorders 
      and suppress immune responses, which can culminate in bacterial pneumonia. 
      Following acute infection, BoHV-1 establishes lifelong latency in sensory neurons 
      present in trigeminal ganglia (TG) and unknown cells in pharyngeal tonsil. 
      Latently infected calves consistently reactivate from latency after an 
      intravenous injection of the synthetic corticosteroid dexamethasone (DEX), which 
      mimics the effects of stress. The immediate early transcription unit 1 (IEtu1) 
      promoter drives expression of infected cell protein 0 (bICP0) and bICP4, two key 
      viral transcriptional regulators. The IEtu1 promoter contains two functional 
      glucocorticoid receptor (GR) response elements (GREs), and this promoter is 
      transactivated by GR, DEX, and certain Kruppel transcription factors that 
      interact with GC-rich motifs, including consensus specificity protein 1 (Sp1) 
      binding sites. Based on these observations, we hypothesized that Sp1 stimulates 
      productive infection and transactivates key BoHV-1 promoters. DEX treatment of 
      latently infected calves increased the number of Sp1(+) TG neurons and cells in 
      pharyngeal tonsil indicating that Sp1 expression is induced by stress. Silencing 
      Sp1 protein expression with siRNA or mithramycin A, a drug that preferentially 
      binds GC-rich DNA, significantly reduced BoHV-1 replication. Moreover, BoHV-1 
      infection of permissive cells increased Sp1 steady-state protein levels. In 
      transient transfection studies, GR and Sp1 cooperatively transactivate IEtu1 
      promoter activity unless both GREs are mutated. Co-immunoprecipitation studies 
      revealed that GR and Sp1 interact in mouse neuroblastoma cells (Neuro-2A) 
      suggesting this interaction stimulates IEtu1 promoter activity. Collectively, 
      these studies suggested that the cellular transcription factor Sp1 enhances 
      productive infection and stress-induced BoHV-1 reactivation from 
      latency.IMPORTANCEFollowing acute infection, bovine alphaherpesvirus 1 (BoHV-1) 
      establishes lifelong latency in sensory neurons in trigeminal ganglia (TG) and 
      pharyngeal tonsil. The synthetic corticosteroid dexamethasone consistently 
      induces BoHV-1 reactivation from latency. The number of TG neurons and cells in 
      pharyngeal tonsil expressing the cellular transcription factor specificity 
      protein 1 (Sp1) protein increases during early stages of dexamethasone-induced 
      reactivation from latency. Silencing Sp1 expression impairs BoHV-1 replication in 
      permissive cells. Interestingly, mithramycin A, a neuroprotective antibiotic that 
      preferentially binds GC-rich DNA, impairs Sp1 functions and reduces BoHV-1 
      replication suggesting that it is a potential antiviral drug. The glucocorticoid 
      receptor (GR) and Sp1 cooperatively transactivate the BoHV-1 immediate early 
      transcript unit 1 (IEtu1) promoter, which drives expression of infected cell 
      protein 0 (bICP0) and bICP4. Mithramycin A also reduced Sp1- and GR-mediated 
      transactivation of the IEtu1 promoter. These studies revealed that GR and Sp1 
      trigger viral gene expression and replication following stressful stimuli.
FAU - El-Mayet, Fouad S
AU  - El-Mayet FS
AUID- ORCID: 0000-0003-3133-3935
AD  - Department of Veterinary Pathobiology, Oklahoma State University, College of 
      Veterinary Medicine, Stillwater, Oklahoma, USA.
AD  - Department of Virology, Benha University, Faculty of Veterinary Medicine, Benha, 
      Egypt.
FAU - Jones, Clinton
AU  - Jones C
AUID- ORCID: 0000-0002-6656-4971
AD  - Department of Veterinary Pathobiology, Oklahoma State University, College of 
      Veterinary Medicine, Stillwater, Oklahoma, USA.
LA  - eng
GR  - P20 GM103648/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20231212
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Adrenal Cortex Hormones)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - 9007-49-2 (DNA)
RN  - 97666-60-9 (mithramycin A)
RN  - NIJ123W41V (Plicamycin)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 0 (Transcription Factors)
RN  - 0 (Viral Proteins)
RN  - 0 (Sp1 Transcription Factor)
SB  - IM
MH  - Animals
MH  - Cattle
MH  - Mice
MH  - Adrenal Cortex Hormones/metabolism
MH  - Dexamethasone/pharmacology
MH  - DNA/metabolism
MH  - *Herpesviridae Infections
MH  - *Herpesvirus 1, Bovine/physiology
MH  - Plicamycin/analogs & derivatives
MH  - *Receptors, Glucocorticoid/genetics/metabolism
MH  - Transcription Factors/metabolism
MH  - Viral Proteins/metabolism
MH  - *Sp1 Transcription Factor/metabolism
PMC - PMC10804982
OTO - NOTNLM
OT  - BoHV-1
OT  - Sp1
OT  - glucocorticoid receptor
OT  - mithramycin A
OT  - stress response
COIS- The authors declare no conflict of interest.
EDAT- 2023/12/12 12:42
MHDA- 2024/01/24 06:43
PMCR- 2024/06/12
CRDT- 2023/12/12 09:03
PHST- 2024/06/12 00:00 [pmc-release]
PHST- 2024/01/24 06:43 [medline]
PHST- 2023/12/12 12:42 [pubmed]
PHST- 2023/12/12 09:03 [entrez]
AID - 01436-23 [pii]
AID - jvi.01436-23 [pii]
AID - 10.1128/jvi.01436-23 [doi]
PST - ppublish
SO  - J Virol. 2024 Jan 23;98(1):e0143623. doi: 10.1128/jvi.01436-23. Epub 2023 Dec 12.