Bovine α-herpesvirus 1 replication and immediate early transcription unit 1 promoter are jointly stimulated by glucocorticoid receptor and DNA-dependent ATPases.

Abstract

Bovine α-herpesvirus 1 (BoHV-1) is a significant viral pathogen in cattle and cofactor of bovine respiratory disease (BRD), a polymicrobial disease. Annually, BRD directly costs the U.S. cattle industry ~$1 billion. Following acute infection, BoHV-1 establishes latency in sensory neurons in trigeminal ganglia, non-neuronal cells in pharyngeal tonsil and certain neurons in the brain. The synthetic corticosteroid dexamethasone (DEX) consistently induces reactivation from latency. The immediate early transcription unit 1 (IEtu1) promoter drives expression of two important viral transcriptional regulatory proteins, infected cell protein 0 (bICP0) and bICP4. An early promoter also drives bICP0 expression. The IEtu1 promoter is activated by the glucocorticoid receptor (GR) and other stress-induced cellular transcription factors because it contains two functional glucocorticoid response elements (GREs). Brahma (BRM) and Brahma-related gene 1 (BRG1) are associated with the SWItch/Sucrose-NonFermentable chromatin remodelling complex. Since BRM and BRG1 interact with GR, we hypothesized that BRG1 and/or BRM stimulate viral gene expression and replication. GR and BRG1 or BRM, cooperatively transactivated an IEtu1 cis-regulatory module that contains both GREs. BoHV-1 replication was also significantly reduced by a BRG1 and/or BRM siRNA or a specific BRG1 and BRM inhibitor (BRM014). Chromatin immunoprecipitation studies revealed that BRG1 occupies IEtu1 promoter sequences only when cells express GR and are treated with DEX. In summary, these studies revealed that GR and the BRG1/BRM chromatin-remodelling proteins cooperatively transactivated the IEtu1 promoter and stimulated BoHV-1 productive infection.