Epstein-Barr Virus BZLF1-Mediated Downregulation of Proinflammatory Factors Is Essential for Optimal Lytic Viral Replication
Epstein-Barr Virus BZLF1-Mediated Downregulation of Proinflammatory Factors Is Essential for Optimal Lytic Viral Replication
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Epstein-Barr 病毒 BZLF1 介导的促炎因子下调对于最佳裂解病毒复制至关重要
DOI：
10.1128/jvi.01921-15
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发表时间：
2015-11
影响因子：
5.4
通讯作者：
Kuang Ersheng
中科院分区：
文献类型：
--
作者：
Li Yuqing;Long Xubing;Huang Lu;Yang Mengtian;Yuan Yan;Wang Yan;Delecluse Henri-Jacques;Kuang Ersheng
摘要炎症因子的分泌增加与潜伏性EB病毒（EBV）感染和EBV相关疾病的病理学有关;然而，在裂解性EBV周期中炎症反应及其生物学意义的知识仍然难以捉摸。在这里，我们证明了立即早期转录激活因子BZLF 1通过结合TNF-α的启动子并阻止NF-κB激活来抑制促炎因子肿瘤坏死因子α（TNF-α）。BZLF 1 Δ207-210突变体在蛋白质-蛋白质结合结构域中缺失4个氨基酸（aa），不能抑制促炎因子TNF-α和γ干扰素（IFN-γ），并且在EBV裂解基因表达期间减少具有完全转录活性的病毒DNA复制。TNF-α耗竭恢复了BZLF 1 Δ207-210介导的病毒复制。此外，TNF-α和IFN-γ中和抗体的组合恢复了BZLF 1 Δ207-210介导的病毒复制，表明BZLF 1主要通过抑制裂解周期中TNF-α和IFN-γ的分泌来减弱抗病毒应答以帮助最佳裂解复制。这些结果表明，EBV BZLF 1减弱促炎反应，以促进病毒复制。重要性促炎反应是复杂炎症表型后的抗病毒和抗癌策略。潜伏性EB病毒（EBV）感染与多种严重疾病中炎性因子分泌升高密切相关，而裂解性EBV周期期间的炎性反应尚未建立。在这里，我们证明BZLF 1作为炎症因子TNF-α和IFN-γ的转录抑制因子，并证实BZLF 1促进的逃避TNF-α和IFN-γ的反应，在EBV裂解的生命周期是需要最佳的病毒复制。这一发现意味着EBV裂解周期采用独特的策略来逃避抗病毒炎症反应。
ABSTRACT Elevated secretion of inflammatory factors is associated with latent Epstein-Barr virus (EBV) infection and the pathology of EBV-associated diseases; however, knowledge of the inflammatory response and its biological significance during the lytic EBV cycle remains elusive. Here, we demonstrate that the immediate early transcriptional activator BZLF1 suppresses the proinflammatory factor tumor necrosis factor alpha (TNF-α) by binding to the promoter of TNF-α and preventing NF-κB activation. A BZLF1Δ207-210 mutant with a deletion of 4 amino acids (aa) in the protein-protein binding domain was not able to inhibit the proinflammatory factors TNF-α and gamma interferon (IFN-γ) and reduced viral DNA replication with complete transcriptional activity during EBV lytic gene expression. TNF-α depletion restored the viral replication mediated by BZLF1Δ207-210. Furthermore, a combination of TNF-α- and IFN-γ-neutralizing antibodies recovered BZLF1Δ207-210-mediated viral replication, indicating that BZLF1 attenuates the antiviral response to aid optimal lytic replication primarily through the inhibition of TNF-α and IFN-γ secretion during the lytic cycle. These results suggest that EBV BZLF1 attenuates the proinflammatory responses to facilitate viral replication. IMPORTANCE The proinflammatory response is an antiviral and anticancer strategy following the complex inflammatory phenotype. Latent Epstein-Barr virus (EBV) infection strongly correlates with an elevated secretion of inflammatory factors in a variety of severe diseases, while the inflammatory responses during the lytic EBV cycle have not been established. Here, we demonstrate that BZLF1 acts as a transcriptional suppressor of the inflammatory factors TNF-α and IFN-γ and confirm that BZLF1-facilitated escape from the TNF-α and IFN-γ response during the EBV lytic life cycle is required for optimal viral replication. This finding implies that the EBV lytic cycle employs a distinct strategy to evade the antiviral inflammatory response.
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影响因子：
14.9
作者：
Wang X;Spandidos A;Wang H;Seed B
通讯作者：
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影响因子：
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作者：
Kong QL;Hu LJ;Cao JY;Huang YJ;Xu LH;Liang Y;Xiong D;Guan S;Guo BH;Mai HQ;Chen QY;Zhang X;Li MZ;Shao JY;Qian CN;Xia YF;Song LB;Zeng YX;Zeng MS
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Zeng MS
影响因子：
13.6
作者：
Donghang Zheng;Hao Chen;M. Bartee;Jennifer M Williams;J. Davids;E. Huang;J. Moreb;A. Lucas
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Donghang Zheng;Hao Chen;M. Bartee;Jennifer M Williams;J. Davids;E. Huang;J. Moreb;A. Lucas
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作者：
M. Tsai;A. Raykova;O. Klinke;Katharina Bernhardt;Kathrin Gärtner;C. Leung;K. Geletneky;S. Sertel
通讯作者：
M. Tsai;A. Raykova;O. Klinke;Katharina Bernhardt;Kathrin Gärtner;C. Leung;K. Geletneky;S. Sertel
影响因子：
5.4
作者：
Morrison, TE;Mauser, A;Kenney, SC
通讯作者：
Kenney, SC