Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA.
J Virol. 2019 Apr 17;93(9). doi: 10.1128/JVI.02246-18. Print 2019 May 1.
Herpes simplex virus 1 (HSV-1) cycles between phases of latency in sensory neurons and replication in mucosal sites. HSV-1 encodes two key proteins that antagonize the shutdown of host translation, US11 through preventing PKR activation and ICP34.5 through mediating dephosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). While profound attenuation of ICP34.5 deletion mutants has been repeatedly demonstrated, a role for US11 in HSV-1 pathogenesis remains unclear. We therefore generated an HSV-1 strain 17 US11-null virus and examined its properties and In U373 glioblastoma cells, US11 cooperated with ICP34.5 to prevent eIF2α phosphorylation late in infection. However, the effect was muted in human corneal epithelial cells (HCLEs), which did not accumulate phosphorylated eIF2α unless both US11 and ICP34.5 were absent. Low levels of phosphorylated eIF2α correlated with continued protein synthesis and with the ability of virus lacking US11 to overcome antiviral immunity in HCLE and U373 cells. Neurovirulence following intracerebral inoculation of mice was not affected by the deletion of US11. In contrast, the time to endpoint criteria following corneal infection was greater for the US11-null virus than for the wild-type virus. Replication in trigeminal ganglia and periocular tissue was promoted by US11, as was periocular disease. The establishment of latency and the frequency of virus reactivation from trigeminal ganglia were unaffected by US11 deletion, although emergence of the US11-null virus occurred with slowed kinetics. Considered together, the data indicate that US11 facilitates the countering of antiviral response of infected cells and promotes the efficient emergence of virus following reactivation. Alphaherpesviruses are ubiquitous DNA viruses and include the human pathogens herpes simplex virus 1 (HSV-1) and HSV-2 and are significant causes of ulcerative mucosal sores, infectious blindness, encephalitis, and devastating neonatal disease. Successful primary infection and persistent coexistence with host immune defenses are dependent on the ability of these viruses to counter the antiviral response. HSV-1 and HSV-2 and other primate viruses within the genus encode US11, an immune antagonist that promotes virus production by preventing shutdown of protein translation. Here we investigated the impact of US11 deletion on HSV-1 growth and pathogenesis This work supports a role for US11 in pathogenesis and emergence from latency, elucidating immunomodulation by this medically important cohort of viruses.
单纯疱疹病毒 1（HSV-1）在感觉神经元中潜伏和在黏膜部位复制之间循环。HSV-1 编码两种关键蛋白，通过阻止 PKR 激活和 ICP34.5 介导真核起始因子 2（eIF2α）α亚基的去磷酸化来拮抗宿主翻译的关闭。虽然 ICP34.5 缺失突变体的严重衰减已被反复证明，但 US11 在 HSV-1 发病机制中的作用仍不清楚。因此，我们生成了一株 HSV-1 17 US11 缺失病毒，并研究了其特性和致病性。在 U373 神经胶质瘤细胞中，US11 与 ICP34.5 合作，在感染后期防止 eIF2α磷酸化。然而，在人角膜上皮细胞（HCLE）中，这种作用被减弱，除非同时缺失 US11 和 ICP34.5，否则 HCLE 细胞不会积累磷酸化的 eIF2α。低水平的磷酸化 eIF2α与持续的蛋白质合成以及缺乏 US11 的病毒在 HCLE 和 U373 细胞中克服抗病毒免疫的能力相关。用 ICP34.5 缺失病毒感染小鼠后，其神经毒力不受影响。相反，与野生型病毒相比，角膜感染后达到终点标准的时间更长。US11 促进三叉神经节和眼周组织中的复制，也促进眼周疾病。潜伏的建立和从三叉神经节重新激活病毒的频率不受 US11 缺失的影响，尽管 US11 缺失病毒的出现速度较慢。综合考虑，这些数据表明 US11 有助于对抗受感染细胞的抗病毒反应，并促进病毒在重新激活后有效出现。α疱疹病毒是无处不在的 DNA 病毒，包括人类病原体单纯疱疹病毒 1（HSV-1）和 HSV-2，是溃疡性黏膜溃疡、传染性失明、脑炎和毁灭性新生儿疾病的重要原因。成功的初次感染和与宿主免疫防御的持续共存取决于这些病毒对抗抗病毒反应的能力。HSV-1 和 HSV-2 以及属内的其他灵长类动物病毒都编码 US11，这是一种免疫拮抗剂，通过防止蛋白质翻译关闭来促进病毒的产生。在这里，我们研究了 US11 缺失对 HSV-1 生长和发病机制的影响。这项工作支持了 US11 在发病机制和从潜伏中出现的作用，阐明了这群具有重要医学意义的病毒的免疫调节作用。
