{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T02:53:51Z","timestamp":1784170431695,"version":"3.55.0"},"reference-count":70,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T00:00:00Z","timestamp":1705968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/ASMCopyrightv2"},{"start":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T00:00:00Z","timestamp":1705968000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"USDA | National Institute of Food and Agriculture","award":["2018-06668"],"award-info":[{"award-number":["2018-06668"]}]},{"name":"USDA | National Institute of Food and Agriculture","award":["2021-67015"],"award-info":[{"award-number":["2021-67015"]}]},{"name":"HHS | NIH | NIH Office of the Director","award":["P20GM103648"],"award-info":[{"award-number":["P20GM103648"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2024,1,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            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 Kr\u00fcppel 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\n            <jats:sup>+<\/jats:sup>\n            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.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>Following 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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.01436-23","type":"journal-article","created":{"date-parts":[[2023,12,12]],"date-time":"2023-12-12T14:00:26Z","timestamp":1702389626000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["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"],"prefix":"10.1128","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3133-3935","authenticated-orcid":false,"given":"Fouad S.","family":"El-mayet","sequence":"first","affiliation":[{"name":"Department of Veterinary Pathobiology, Oklahoma State University, College of Veterinary Medicine, Stillwater, Oklahoma, USA"},{"name":"Department of Virology, Benha University, Faculty of Veterinary Medicine, Benha, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6656-4971","authenticated-orcid":false,"given":"Clinton","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, Oklahoma State University, College of Veterinary Medicine, Stillwater, Oklahoma, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1017\/S146625230700134X"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cvfa.2020.03.008"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.63.4.1525-1530.1989"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-71-2-369"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1089\/vim.1987.1.287"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501463102"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1089\/vim.1997.10.21"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1089\/vim.1993.6.273"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0168-1702(97)00128-7"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.10.8657-8668.1999"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2017.03.016"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.2460\/javma.241.2.189"},{"key":"e_1_3_2_14_2","first-page":"259","article-title":"Abortifacient vaccines and bovine herpesvirus-1","volume":"237","author":"O\u2019Toole D","year":"2010","unstructured":"O\u2019Toole D, Van Campen H. 2010. 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