Herpes Simplex Virus Type 2 Immediate Early Protein ICP27 Inhibits IFN-β Production in Mucosal Epithelial Cells by Antagonizing IRF3 Activation
Herpes Simplex Virus Type 2 Immediate Early Protein ICP27 Inhibits IFN-β Production in Mucosal Epithelial Cells by Antagonizing IRF3 Activation
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单纯疱疹病毒 2 型立即早期蛋白 ICP27 通过拮抗 IRF3 激活抑制粘膜上皮细胞中 IFN-β 的产生
DOI：
10.3389/fimmu.2019.00290
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发表时间：
2019-02-26
影响因子：
7.3
通讯作者：
Hu, Qinxue
中科院分区：
文献类型：
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作者：
Guan, Xinmeng;Zhang, Mudan;Hu, Qinxue
单纯疱疹病毒2型（HSV-2）是生殖器疱疹的主要原因，感染常见于下生殖道。虽然神经细胞和免疫细胞可以被感染，上皮细胞和角化细胞是主要的HSV-2靶细胞。2型单纯疱疹病毒通过逃避宿主免疫系统建立潜伏期，其感染也可增加1型艾滋病毒性传播的风险。我们之前的研究发现，HSV-2即时早期蛋白ICP22通过干扰IRF3途径抑制ifn - β的产生。然而，icp22缺失的HSV-2并没有完全丧失抑制ifn - β诱导的能力，这表明其他病毒成分参与了这一过程。在本研究中，通过体外宫颈移植模型，我们首次证明HSV-2确实可以抑制人粘膜组织中ifn - β的诱导。我们进一步发现HSV-2即时早期蛋白ICP27是一种有效的ifn - β拮抗剂。ICP27显著抑制仙台病毒或多肌苷-多胞酸诱导的人粘膜上皮细胞中ifn - β的产生，表明ICP27在mRNA和蛋白水平上抑制ifn - β启动子的激活和ifn - β的产生。进一步的研究表明，ICP27直接与IRF3结合，抑制其磷酸化和核易位，从而抑制ifn - β诱导。我们的研究结果为HSV-2粘膜免疫逃避的分子机制提供了见解，并为HSV-2粘膜疫苗的设计提供了信息。
Herpes simplex virus type 2 (HSV-2) is the main cause of genital herpes and infections are common in the lower genital tract. Although neuronal and immune cells can be infected, epithelial cells, and keratinocytes are the primary HSV-2 target cells. HSV-2 establishes latency by evading the host immune system and its infection can also increase the risk of HIV-1 sexual transmission. Our pervious study found that HSV-2 immediate early protein ICP22, inhibited IFN-beta production by interfering with the IRF3 pathway. However, ICP22-null HSV-2 did not completely lose the capability of suppressing IFN-beta induction, suggesting the involvement of other viral components in the process. In this study, by using an ex vivo cervical explant model, we first demonstrated that HSV-2 can indeed inhibit IFN-beta induction in human mucosal tissues. We further identified HSV-2 immediate early protein ICP27 as a potent IFN-beta antagonist. ICP27 significantly suppresses the Sendai virus or polyinosinic-polycytidylic acid-induced IFN-beta production in human mucosal epithelial cells, showing that ICP27 inhibits the IFN-beta promoter activation, and IFN-beta production at both mRNA and protein levels. Additional studies revealed that ICP27 directly associates with IRF3 and inhibits its phosphorylation and nuclear translocation, resulting in the inhibition of IFN-beta induction. Our findings provide insights into the molecular mechanism underlying HSV-2 mucosal immune evasion, and information for the design of HSV-2 mucosal vaccines.