Transcriptome profiling reveals that the host BRD4 protein facilitates African swine fever virus infection and suppresses inflammatory cytokine expression by downregulating transcriptional regulatory signaling pathways

Abstract

The African swine fever virus (ASFV), a complex DNA virus belonging to the Asfarviridae family, is a significant threat to the global swine industry because of its high mortality rates and impact on international trade. The establishment of a stable and efficient cell culture model of ASFV in vitro is helpful for the development of effective vaccines. Several passaged cell lines supporting ASFV replication have been reported to meet the scientific purpose of serial passage of ASFV to a certain extent, but it remains to be determined whether gene expression is lost or whether immunogenicity changes after serial passage of the virus. It is also unclear these edited cell lines how to affect ASFV replication. In our previous study, 3D4/21 cells were transduced with a lentivirus packaging system to express the BD1/2 domain of bromodomain-containing protein 4 (BRD4-BD1/2) and establish a 3D4/21-BD1/2 cell line, which efficiently increased ASFV replication. In this study, the role of bromodomain-containing protein 4 (BRD4), particularly its BD1/2 domains,in enhancing ASFV replication was investigated using an engineered 3D4/21 cell line. Through RNA-Seq transcriptomic analysis, we revealed that the host BRD4 protein facilitates ASFV infection and suppresses key transcription factors (CDK9 and p-CDK9) and inflammatory cytokine expression by downregulating transcriptional regulatory signaling pathways and suppressing innate immune responses. This dual mechanism of BRD4-BD1/2 in promoting ASFV immune evasion and adaptation underscores the virus’s strategic exploitation of host epigenetic factors. These findings provide valuable insights into viral pathogenesis and identify potential therapeutic targets, paving the way for future antiviral strategies.