The periodontal pathogen Porphyromonas gingivalis induces the Epstein-Barr virus lytic switch transactivator ZEBRA by histone modification
The periodontal pathogen Porphyromonas gingivalis induces the Epstein-Barr virus lytic switch transactivator ZEBRA by histone modification
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DOI：
10.1016/j.biochi.2011.12.001
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发表时间：
2012-03-01
期刊：
影响因子：
3.9
通讯作者：
Ochiai, Kuniyasu
中科院分区：
文献类型：
--
作者：
Imai, Kenichi;Inoue, Harumi;Ochiai, Kuniyasu
EB病毒（EBV）是一种普遍存在的人类疱疹病毒，其通常导致B细胞的潜伏感染。EBV BZLF1基因产物ZEBRA是从潜伏期到裂解性复制周期转变的主要调节因子。在潜伏状态下，组蛋白去乙酰化酶（HDAC）引起的BZLF1启动子中组蛋白的低乙酰化主要参与维持EBV潜伏期。虽然调节潜伏期和裂解性复制之间的转换的机制一直是EBV感染的中心研究焦点，但HDAC抑制和病毒潜伏期破坏之间的因果关系尚不清楚。牙周病是一种复杂的慢性炎症性疾病，由口腔厌氧菌引起的龈下感染，典型的是牙龈卟啉单胞菌。牙周病在世界范围内发生，是人类最普遍的微生物疾病之一。在这项研究中，我们研究了牙龈卟啉单胞菌感染对EBV再激活的生物学效应，发现牙龈卟啉单胞菌诱导ZEBRA的表达。这种活性与细菌培养物的上清液有关，但与其他细菌组分如脂多糖或菌毛无关。我们证明，牙龈卟啉单胞菌的培养上清液，其中含有高浓度的丁酸，抑制HDAC，从而增加组蛋白乙酰化和BZLF1基因的转录活性。染色质免疫沉淀试验表明，HDAC存在于BZLF1启动子在潜伏状态，他们解离的启动子伴随着协会的乙酰化组蛋白H3，刺激后培养上清液牙龈卟啉单胞菌。因此，牙龈卟啉单胞菌通过染色质修饰诱导EBV再活化，而细菌代谢产物丁酸负责这种作用。这些研究结果表明，牙周病是感染者EBV再激活的危险因素，因此可能有助于EBV相关疾病的进展。(C)2011年爱思唯尔马森SAS。All rights reserved.
Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that usually results in latent infection of B cells. The EBV BZLF1 gene product ZEBRA is a master regulator of the transition from latency to the lytic replication cycle. In the latent state, hypoacetylation of histone proteins in the BZLF1 promoter by histone deacetylases (HDACs) is primarily involved in maintaining EBV latency. Although the mechanism that regulates the switch between latency and lytic replication has been a central research focus in EBV infection, the causal link between HDAC inhibition and the disruption of viral latency is not well understood. Periodontal disease is a complex chronic inflammatory disease caused by subgingival infection with oral anaerobic bacteria, typically Porphyromonas gingivalis. Periodontal disease occurs worldwide and is among the most prevalent microbial diseases in humans. In this study, we examined the biological effect of P. gingivalis infection on EBV reactivation and found that P. gingivalis induced expression of ZEBRA. This activity was associated with supernatant from bacterial culture, but not with other bacterial components such as lipopolysaccharide or fimbriae. We demonstrated that culture supernatant from P. gingivalis, which contained high concentrations of butyric acid, inhibited HDACs, thus increasing histone acetylation and the transcriptional activity of the BZLF1 gene. Chromatin immunoprecipitation assays revealed that HDACs were present in the BZLF1 promoter during latent state and that they were dissociated from the promoter concomitantly with the association of acetylated histone H3, upon stimulation by culture supernatant from P. gingivalis. Thus, P gingivalis induced EBV reactivation via chromatin modification, and butyric acid a bacterial metabolite was responsible for this effect. These findings suggest that periodontal disease is a risk factor for EBV reactivation in infected individuals and might therefore contribute to progression of EBV-related diseases. (C) 2011 Elsevier Masson SAS. All rights reserved.