Department of Microbiology and Immunology Institute, Mount Sinai School of Medicine, New York, New York, USA.
PLoS One. 2010 Feb 18;5(2):e8684. doi: 10.1371/journal.pone.0008684.
Molecular pathways underlying the activation of dendritic cells (DCs) in response to Herpes Simplex Virus type 1 (HSV-1) are poorly understood. Removal of the HSV virion host shut-off (vhs) protein relieves a block to DC activation observed during wild-type infection. In this study, we utilized a potent DC stimulatory HSV-1 recombinant virus lacking vhs as a tool to investigate the mechanisms involved in the activation of DCs by HSV-1. We report that the release of pro-inflammatory cytokines by conventional DC (cDC) during HSV-1 infection is triggered by both virus replication-dependent and replication-independent pathways. Interestingly, while vhs is capable of inhibiting the release of cytokines during infection of human and mouse cDCs, the secretion of cytokines by plasmacytoid DC (pDC) is not affected by vhs. These data prompted us to postulate that infection of cDCs by HSV triggers a TLR independent pathway for cDC activation that is susceptible to blockage by the vhs protein. Using cDCs isolated from mice deficient in both the TLR adaptor protein MyD88 and TLR3, we show that HSV-1 and the vhs-deleted virus can activate cDCs independently of TLR signaling. In addition, virion-associated vhs fails to block cDC activation in response to treatment with TLR agonists, but it efficiently blocked cDC activation triggered by the paramyxoviruses Sendai Virus (SeV) and Newcastle Disease Virus (NDV). This block to SeV- and NDV-induced activation of cDC resulted in elevated SeV and NDV viral gene expression indicating that infection with HSV-1 enhances the cell's susceptibility to other pathogens through the action of vhs. Our results demonstrate for the first time that a viral protein contained in the tegument of HSV-1 can block the induction of DC activation by TLR-independent pathways of viral recognition.
单纯疱疹病毒 1 型（HSV-1）激活树突状细胞（DC）的分子途径知之甚少。去除 HSV 病毒体宿主关闭（vhs）蛋白可缓解野生型感染中观察到的 DC 激活受阻。在这项研究中，我们利用缺乏 vhs 的强效 HSV-1 重组病毒作为工具，研究 HSV-1 激活 DC 的相关机制。我们报告称，在 HSV-1 感染过程中，常规 DC（cDC）释放促炎细胞因子是由病毒复制依赖性和非复制依赖性途径触发的。有趣的是，虽然 vhs 能够抑制人源和鼠源 cDC 感染期间细胞因子的释放，但 vhs 不影响浆细胞样 DC（pDC）细胞因子的分泌。这些数据促使我们推测，HSV 感染 cDC 会触发一种 TLR 非依赖性途径来激活 cDC，而 vhs 蛋白可阻断该途径。使用缺乏 TLR 衔接蛋白 MyD88 和 TLR3 的 cDC 进行研究，我们表明 HSV-1 和缺失 vhs 的病毒可以独立于 TLR 信号激活 cDC。此外，病毒体相关的 vhs 无法阻断 TLR 激动剂处理后 cDC 的激活，但它可有效阻断副粘病毒仙台病毒（SeV）和新城疫病毒（NDV）引发的 cDC 激活。这种对 SeV 和 NDV 诱导的 cDC 激活的阻断导致 SeV 和 NDV 病毒基因表达升高，表明 HSV-1 感染通过 vhs 的作用增强了细胞对其他病原体的易感性。我们的结果首次表明，HSV-1 衣壳中的一种病毒蛋白可阻断 TLR 非依赖性病毒识别途径诱导的 DC 激活。
