College of Animal Sciences and Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China.
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Jiangsu Province, P.R. China.
PLoS Pathog. 2020 Mar 24;16(3):e1008429. doi: 10.1371/journal.ppat.1008429. eCollection 2020 Mar.
Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.
染色质动力学受表观遗传修饰调控，对基因组稳定性和基因表达至关重要。各种表观遗传机制已被确定在人类疾病的发病机制中。在这里，我们通过 GFP 报告基因检测研究了十种表观遗传药物对伪狂犬病毒（PRV）感染的影响。溴结构域蛋白 4（BRD4）抑制剂在癌症方面比病毒感染受到更多关注，研究发现其对 PRV 以及一系列 DNA 和 RNA 病毒均具有显著的抗病毒活性。我们进一步证明 BRD4 抑制可增强强大的先天免疫反应。BRD4 抑制还可使染色质结构解聚，并诱导 DNA 损伤反应，从而触发 cGAS 介导的先天免疫激活，并增加宿主对病毒感染的抵抗力，无论是在体外还是体内。从机制上讲，BRD4 抑制对病毒感染的抑制作用主要归因于病毒附着的减弱。我们的研究结果揭示了 BRD4 抑制抑制病毒感染的独特机制，并指出其在病毒感染性疾病方面具有潜在的治疗价值。
