Zhao Yaru, Niu Qingli, Yang Saixia, Yang Jifei, Zhang Zhonghui, Geng Shuxian, Fan Jie, Liu Zhijie, Guan Guiquan, Liu Zhiqing, Zhou Jia, Hu Haitao, Luo Jianxun, Yin Hong
African Swine Fever Regional Laboratory, and State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, People's Republic of China.
Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao, China.
Microbiol Spectr. 2022 Aug 31;10(4):e0241921. doi: 10.1128/spectrum.02419-21. Epub 2022 Jun 27.
African swine fever (ASF), an acute, severe, highly contagious disease caused by African swine fever virus (ASFV) infection in domestic pigs and boars, has a mortality rate of up to 100%. Because effective vaccines and treatments for ASF are lacking, effective control of the spread of ASF remains a great challenge for the pig industry. Host epigenetic regulation is essential for the viral gene transcription. Bromodomain and extraterminal (BET) family proteins, including BRD2, BRD3, BRD4, and BRDT, are epigenetic "readers" critical for gene transcription regulation. Among these proteins, BRD4 recognizes acetylated histones via its two bromodomains (BD1 and BD2) and recruits transcription factors, thereby playing a pivotal role in transcriptional regulation and chromatin remodeling during viral infection. However, how BET/BRD4 regulates ASFV replication and gene transcription is unknown. Here, we randomly selected 12 representative BET family inhibitors and compared their effects on ASFV infection in pig primary alveolar macrophages (PAMs). These were found to inhibit viral infection by interfering viral replication. The four most effective inhibitors (ARV-825, ZL0580, I-BET-762, and PLX51107) were selected for further antiviral activity analysis. These BET/BRD4 inhibitors dose dependently decreased the ASFV titer, viral RNA transcription, and protein production in PAMs. Collectively, we report novel function of BET/BRD4 inhibitors in inducing suppression of ASFV infection, providing insights into the role of BET/BRD4 in the epigenetic regulation of ASFV and potential new strategies for ASF prevention and control. Due to the continuing spread of the ASFV in the world and the lack of commercial vaccines, the development of improved control strategies, including antiviral drugs, is urgently needed. BRD4 is an important epigenetic factor and has been commonly used for drug development for tumor treatment. Furthermore, the latest research showed that BET/BRD4 inhibition could suppress replication of virus. In this study, we first showed the inhibitory effect of agents targeting BET/BRD4 on ASFV infection with no significant host cytotoxicity. Then, we found four BET/BRD4 inhibitors that can inhibit ASFV replication, RNA transcription, and protein synthesis. Our findings support the hypothesis that BET/BRD4 can be considered as attractive host targets in antiviral drug discovery against ASFV.
非洲猪瘟（ASF）是一种由非洲猪瘟病毒（ASFV）感染家猪和野猪引起的急性、严重且高度传染性疾病，死亡率高达100%。由于缺乏针对ASF的有效疫苗和治疗方法，有效控制ASF的传播对养猪业来说仍然是一项巨大挑战。宿主表观遗传调控对病毒基因转录至关重要。含溴结构域和额外末端（BET）家族蛋白，包括BRD2、BRD3、BRD4和BRDT，是对基因转录调控至关重要的表观遗传“读取器”。在这些蛋白中，BRD4通过其两个含溴结构域（BD1和BD2）识别乙酰化组蛋白并招募转录因子，从而在病毒感染期间的转录调控和染色质重塑中发挥关键作用。然而，BET/BRD4如何调节ASFV复制和基因转录尚不清楚。在此，我们随机选择了12种代表性的BET家族抑制剂，并比较了它们对猪原代肺泡巨噬细胞（PAM）中ASFV感染的影响。发现这些抑制剂通过干扰病毒复制来抑制病毒感染。选择了四种最有效的抑制剂（ARV - 825、ZL0580、I - BET - 762和PLX51107）进行进一步的抗病毒活性分析。这些BET/BRD4抑制剂剂量依赖性地降低了PAM中的ASFV滴度、病毒RNA转录和蛋白质产生。总体而言，我们报告了BET/BRD4抑制剂在诱导抑制ASFV感染方面的新功能，为BET/BRD4在ASFV表观遗传调控中的作用以及ASF预防和控制的潜在新策略提供了见解。由于ASFV在全球持续传播且缺乏商业疫苗，迫切需要开发包括抗病毒药物在内的改进控制策略。BRD4是一种重要的表观遗传因子，已普遍用于肿瘤治疗的药物开发。此外，最新研究表明抑制BET/BRD4可以抑制病毒复制。在本研究中，我们首先展示了靶向BET/BRD4的药物对ASFV感染的抑制作用且对宿主无明显细胞毒性。然后，我们发现了四种能够抑制ASFV复制、RNA转录和蛋白质合成的BET/BRD4抑制剂。我们的研究结果支持这样一种假设，即BET/BRD4可被视为抗ASFV抗病毒药物研发中具有吸引力的宿主靶点。
