2. 四川农业大学 预防兽医研究所, 成都 611130;
3. 四川农业大学 动物疫病与人类健康四川省重点实验室, 成都 611130
2. Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China;
3. Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
疱疹病毒在自然界中广泛分布，可感染哺乳类、禽类、两栖类和无脊椎动物，引起多种疾病。至今已发现的疱疹病毒有100余种，根据病毒的生物学特征和基因组结构，疱疹病毒可分为α、β和γ 3个亚科。其中，α疱疹病毒(alphaherpesvirus)宿主范围最广，可以在感觉神经元建立潜伏感染。α疱疹病毒包括Ⅰ型单纯疱疹病毒(herpes simplex virus type 1, HSV-1)、Ⅱ型单纯疱疹病毒(herpes simplex virus type 2, HSV-2)、伪狂犬病病毒(pseudorabies virus，PRV)、水痘带状疱疹病毒(varicella zoster virus, VZV)和牛疱疹病毒Ⅰ型(bovine herpesvirus type 1，BHV-1)等。
α疱疹病毒是具有囊膜的双链线性DNA病毒，病毒粒子包括核心、衣壳、皮层和囊膜四种结构。在病毒感染过程中，囊膜糖蛋白参与识别宿主细胞膜受体、病毒吸附入侵宿主细胞、病毒从核膜出芽释放、诱导细胞融合和宿主免疫反应等过程。目前已鉴定12种囊膜糖蛋白，分别为gB、gC、gD、gE、gH、gI、gG、gK、gL、gM、gN和gJ，其中gE是由US8基因编码，翻译后经糖基化修饰形成。gE是大多数α疱疹病毒复制的非必需糖蛋白，但能够促进病毒粒子的次级包被[1]、胞间传递[2]，参与免疫逃避[3]，影响神经毒力[4]。本文主要总结了囊膜糖蛋白gE在毒力方面的研究进展，旨在为相关研究提供参考。
1 gE的结构与定位在α疱疹病毒粒子中，囊膜是位于病毒粒子最外层的双层脂质膜结构，其表面有呈放射状排列的纤突，构成病毒粒子表面的抗原决定簇。囊膜糖蛋白gE位于病毒的囊膜上，具有典型的Ⅰ型膜蛋白特征，多肽链跨膜一次，N端在细胞膜外，C端在细胞膜内，分成胞外域、跨膜区及胞内域3个部分。虽然不同α疱疹病毒gE的氨基酸序列同源性较低，但是存在重要的同源区。gE胞内域中有与高尔基体定位相关的磷酸化酸性氨基酸簇[5]、由2个苏氨酸和2个丝氨酸构成的酪蛋白激酶Ⅱ磷酸化序列[6]和酪氨酸内吞基序(YXXL)[7]，其中Y为酪氨酸，X为任意氨基酸，L为疏水性氨基酸。gE胞外域中有与US7基因编码的gI糖蛋白相互作用相关的半胱氨酸富集区域[8]，主要包括2个保守的半胱氨酸区域(C1和C2)，其中C1区域通常含有4个半胱氨酸残基(图 1A)。gE蛋白二级结构中无规则卷曲所占比例较大，含量大于50%，而α-螺旋结构、β-折叠、β-转角含量相对较少(图 1B)。Sprague等[9]通过分析gE和gE/gI-Fc复合物晶体结构，发现gE胞外域的C端是与免疫球蛋白G(immunoglobulin G, IgG) CH2-CH3界面结合的最小区域(图 1C)。
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A. gE蛋白一级结构，包括胞外域(ET)、跨膜区(TM)、胞内域(CT); B. gE蛋白二级结构; C. gE/gI-Fc蛋白带状三维结构(红色为gE胞外域中的IgG结合区域，蓝色为IgG的Fc区域，黄色为gE与gI相互作用的C1区域，彩图见OSID开放科学数据与内容) A. Primary structure of gE protein, including extracellular domain (ET), transmembrane domain (TM), intracellular domain (CT); B. Secondary structure of gE protein; C. Ribbon representation of gE/gI-Fc complex (gE ET is shown in red, Fc is shown in blue and C1 domain is shown in yellow, color pictures are provided in OSID) 图 1 α疱疹病毒gE蛋白结构[9] Fig. 1 Structure of the alphaherpesvirus gE[9] |
病毒核酸进入细胞核后，gE基因在胞核中转录并依赖于宿主蛋白在内质网中表达，随后gE、gI蛋白在内质网以非共价键形成异源二聚体[10]。大多数gE/gI通过胞内域的酪氨酸内吞基序与衔接蛋白AP-1特异性结合后胞吞进入高尔基体[11]。酸弗林蛋白酶酸性氨基酸簇分选蛋白1与gE胞内域的酸性氨基酸簇相互作用影响gE/gI在高尔基体上的分布[12]。在病毒感染晚期gE/gI分布到细胞连接处[2]，出现在细胞的外侧面。
2 gE参与病毒粒子的次级包被、胞间传递而增强病毒毒力α疱疹病毒的复制周期包括病毒吸附、入侵、复制、装配、子代病毒释放等过程。病毒吸附后通过表面的糖蛋白与细胞表面特异性受体识别并相互作用，促进病毒囊膜与细胞膜的融合入侵细胞[13]。随后，无囊膜的病毒粒子通过微管转移靠近细胞核，病毒核酸通过核孔进入细胞核后DNA迅速环化开启核酸的复制，并与病毒的衣壳蛋白组装成核衣壳[14-15]。核衣壳通过与核内膜包裹进行初级包被，进入核间隙。然后，初级包被的囊膜与核外膜融合，核衣壳释放到细胞质，完成去包被过程。在细胞质内获得皮层的核衣壳在高尔基体上以出芽的方式进行二次囊膜包被形成成熟的病毒粒子。最后，囊泡将病毒运送到细胞膜周围，通过膜融合释放病毒(图 2)。在α疱疹病毒中，gE参与病毒粒子的次级包被和胞间传递，通过促进病毒粒子的成熟和在易感细胞间的传播增强病毒毒力。
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1.病毒吸附和入侵；2.无囊膜的病毒粒子进入到细胞核；3.核酸复制，环化；4.组装核衣壳；5.核衣壳在高尔基体的二次囊膜包被，gE与多种皮层蛋白相互作用影响二次囊膜包被(右图)，其中包括：gE与VP22- ICP0相互作用; gE与UL7-UL51:gE与UL11-UL16-UL21相互作用；6.病毒粒子的释放；7.gE/gI定位于细胞外侧连接处，与相邻细胞的受体结合 1. Virus adsorption and invasion; 2.Transfer the capsid to nucleus; 3.DNA replication and cyclization; 4. Assemble capsid; 5. Secondary envelopment at Golgi membranes. Interactions of tegumented capsids with glycoproteins and membrane proteins (Right): gE is shown to interact with VP22-ICP0; gE is shown to interact with UL7-UL51; gE is shown to interact with UL11-UL16-UL21; 6.Exocytosis of mature virions; 7. gE/gI locate at the lateral junction of the cell and bind to the receptor of adjacent cells 图 2 α疱疹病毒gE与皮层蛋白在高尔基体二次囊膜包被过程和胞间传递的作用[33] Fig. 2 Diagrammatic description of gE-tegument protein interactions during cytoplasmic virion envelopment at Golgi and intercellular transmission[33] |
gE胞内域参与核衣壳在高尔基体特定部位的次级包被，将新生病毒粒子选择性分布至细胞连接处，促进病毒在细胞间传播。Farnsworth等[16]在HSV-1 gD基因缺失株的基础上构建了gE胞内域不同区域缺失的病毒，发现缺失第470—495位氨基酸后，大量核衣壳在细胞质中发生聚集。Han等[17]研究表明HSV-1 gE胞内域与UL11的酸性团簇相互作用，在缺失gE胞内域的情况下，UL11包装进病毒粒子的数量至少减少80%；在缺失UL11的情况下，gE包装进病毒粒子中也显著减少87%，核衣壳无法完成次级包被而形成完整的病毒粒子，显著抑制了病毒的释放。
gE胞外域参与胞间传递的过程主要发生在上皮组织和神经组织等极性细胞间[18]。gE胞外域通过受体机制与细胞连接处的组成成分结合，使gE/gI复合物定位于细胞外侧连接处与相邻细胞受体结合，促进感染细胞与临近非感染细胞的融合。Polcicova等[19]将HSV gE胞外域的第277、291、348位氨基酸分别点突变构建成3个突变株，感染细胞后形成与gE全基因缺失株相似的小面积空斑，病毒从角膜到上皮组织的传递受到限制。Berarducci等[8]将VZV gE胞外域中半胱氨酸区域(208—236位氨基酸)突变后gE与gI无法形成复合物，并不同程度影响了gE、gI在受感染细胞膜上的分布和病毒的细胞间扩散。这些研究证明gE胞外域与gI形成复合物促使病毒转移到细胞连接处，通过影响病毒释放到游离的上清介质或直接侵染相邻细胞实现对其他细胞的感染和在细胞间的信号传导，促进病毒的传播。
VZV gE胞外域可以与该病毒的一种受体——胰岛素降解酶(insulin degradation enzyme，IDE)结合。IDE是一种锌金属蛋白酶，可以降解包括胰岛素和淀粉样蛋白在内的许多小蛋白。IDE与gE前体在内质网结合，在病毒感染的早期阶段诱导gE构象发生改变，增加病毒的感染性、稳定性和促进病毒在细胞间的传播[20-22]。gE胞外域的27—90位氨基酸缺失后，gE无法与IDE相互作用，但病毒在小鼠体内T细胞中可以正常复制和传播[23]。可见，VZV gE/IDE在不同类型细胞中发挥不同的功能，这可能与糖蛋白和受体作用机制不同有关。
2.2 gE和其他蛋白共同参与病毒粒子的次级包被、胞间传递gE与3种皮层蛋白UL11、UL16、UL21形成复合物共同促进病毒次级包被，影响细胞融合形成合胞体，使病毒从感染细胞进入相邻非感染细胞。HSV-1gE胞内域和UL16相互作用[24]，但gE与UL16的相互作用很弱，UL11与gE胞内域结合会导致UL16的构象发生改变，促进gE与UL16的相互作用[25]。gE在细胞表面的积累与UL11-UL16-UL21复合物相关，并且每一种皮层蛋白对于gE的功能都是至关重要的，推测gE胞内域与这3种皮层蛋白参与病毒感染后合胞体的形成和胞间传递有关。进一步研究证明细胞质中的肌动蛋白可以与UL11-UL16-UL21相互作用，并通过UL11的高尔基体定位基序将3种皮层蛋白运输到高尔基体与gE共同促进二次囊膜包被，并通过UL11的肉豆蔻酰化和棕榈酰化修饰与脂筏结合，将gE-UL11-UL16-UL21复合物运输至细胞表面，促进细胞融合，介导成熟病毒粒子释放[26-27]。
gE/gI可以通过与皮层蛋白UL7-UL51形成复合物聚集分布在细胞表面，影响病毒感染后细胞的形态和功能，稳定细胞膜局灶性黏连，促进病毒在细胞间扩散。HSV-1 gE-UL7-UL51可以形成复合物并聚集分布在细胞表面连接处，促进病毒组装和在上皮细胞间的传播，UL51缺失后gE无法在细胞连接处累积，合胞体无法形成[28-29]，UL7的167—244位氨基酸缺失后，gE也不能累积在细胞连接处[30]。
gE与VP22相互作用影响病毒在高尔基体的定位和包装。HSV-1 gE/gI的胞内域与gD、VP22相互作用促进病毒粒子次级包被[16]。HSV-1 VP22中缺失14个氨基酸后不能与gE结合，VP22无法定位到高尔基体上，而是在细胞质中弥漫性分布，成熟病毒粒子减少[31]。gE可以与gI、gM、皮层蛋白VP22、ICP0结合形成多组分复合物，gE和gM缺失后VP22和ICP0参与病毒粒子装配的数量减少，导致次级包膜缺陷，病毒产量降低，空斑形成的面积变小[32]，说明gE-VP22-gM-gI-ICP0复合物的形成与病毒增殖和传递有关(图 2)。
3 gE参与免疫逃避而增强病毒毒力HSV gE与IgG的Fc段结合，在空间上阻碍了IgG或Fc依赖的效应细胞接近病毒或被病毒感染的细胞，补体Clq无法与IgG Fc位点发生结合[34-35]，阻断其补体经典途径的激活，保护病毒免受抗体依赖的细胞毒性和抗体依赖细胞介导的吞噬作用等免疫过程[3, 36-38]。HSV-1的gE/gI与人IgG的Fc片段的CH2-CH3位点结合，IgG的抗原结合片段(Fab)识别病毒抗原并结合，形成gE/gI-IgG-抗原三聚体复合物，该复合物又被称为双极桥(bipolar bridging, ABB)[9]。gE/gI与Fc片段的结合位点对pH变化敏感[39]，gE/gI复合物内吞进入酸性核内体可发生解离，解离后的IgG-抗原复合物通过囊泡转运至酸性溶酶体中降解，而gE/gI重新循环至细胞表面[40](图 3)。
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1.细胞表面ABB复合物(gE/gI作为受体与IgG的Fc片段结合，gD结合Fab)被内吞进入核内体中；2. IgG的Fc片段无法与NK细胞、单核细胞、巨噬细胞、粒细胞表面的Fc受体结合，病毒免受抗体依赖的细胞毒性作用；3. IgG的Fc片段无法与补体Clq结合使补体经典激活途径被抑制；4. IgG的Fc片段无法与吞噬细胞的结合，病毒免受抗体依赖细胞介导的吞噬作用；5. lgG-gD复合物进入溶酶体被降解；6. gE/gI重新循环至细胞表面；7. gE/gI逆行转运至高尔基体; 8.gE蛋白通过激活ERK1/2对不同种细胞的磷酸化作用 1. Cell surface ABB complexes (the Fc of IgG bound to gE-gI and the Fabs bound to gD) are endocytosed into endosomes; 2. The gE/gI complex combine with IgG Fc to inhibit the effects of antibody-dependent cell-mediated cytotoxicity; 3. The gE/gI complex combine with IgG Fc to inhibit the classical activation pathway of complement; 4. The Fc fragment of IgG can not bind to phagocytic cells to inhibit the effects of antibody-dependent cellular phagocytosis; 5. The lgG-gD complex enter to the lysosome to be degraded; 6. Free gE/gI recycle back to the cell surface; 7. Free gE/gI could be trafficked via a retrograde pathway to the Golgi network; 8. The gE regulates the phosphorylation of ERK1/2 图 3 gE介导免疫逃逸机制[36, 40] Fig. 3 The model of gE functions in immune escape[36, 40] |
PRV gE可以通过磷酸化激活细胞外信号调节激酶(extracellular regulated protein kinases 1/2, ERK1/2)，增强淋巴细胞的迁移，使T细胞聚集，破坏宿主的信号通路，并且迁移的T细胞可将病毒扩散到其他易感细胞，有助于病毒在体内以及向新宿主的传播[41]。PRV gE胞外域可以结合上皮细胞表面的一种未知的细胞受体激活ERK1/2信号，促进降解促凋亡蛋白Bim，使病毒感染细胞存活时间延长，病毒复制增加，但gE介导的ERK 1/2磷酸化并没有导致T淋巴细胞中Bim的降解[42]。缺失gE、US9、US2和gI部分缺失的PRV疫苗株Bartha株可以使浆细胞样树突状细胞(plasmacytoid dendritic cells, pDC)产生更多的Ⅰ型干扰素，缺失gE的病毒增加pDC中ERK1/2磷酸化促进Ⅰ型干扰素产生，推测这与gE和pDC上的特定抑制性受体相互作用抑制Ⅰ型干扰素的产生有关[43]。疱疹病毒诱导的ERK 1/2磷酸化可能会对不同细胞触发不同的反应(图 3)。
此外，gE还可通过其糖基化修饰完全或部分覆盖住蛋白表面的识别位点，使受感染的细胞不易于被免疫细胞识别进行免疫逃避。VZV gE的O-糖基化修饰的比例与糖基化结构会影响病毒特异性CD4+ T细胞反应以及抗B淋巴细胞的免疫反应[44]。
4 gE通过影响神经侵袭和神经传递增强病毒毒力α疱疹病毒粒子从轴突末端侵入初级神经元，逆行至核周区域后，病毒基因组DNA进入细胞核，立即聚集形成异染色质，建立潜伏性感染[45]。当宿主处于应激或某种特殊状态时被再激活，新合成的病毒主要通过以下两种方式传导：一种是病毒粒子沿轴突正向传递到外周组织，通常是受神经支配的上皮组织，在上皮组织中产生大量的子代病毒，从而扩散到宿主其他组织；另一种是病毒在胞体中沿着轴突或树突向更高级的神经元正向传导，最终通过跨突触传播到达更高级的神经元。在此过程中，病毒通过轴突传播避免了细胞外的免疫反应[46]。
BHV-1通过鼻内和眼部进入机体后，可在三叉神经节建立终身潜伏感染。重新激活后，病毒从神经元胞体转移到鼻和眼角膜的神经末梢。若截短了gE胞内域，转运过程则被阻断[47-48]，说明gE胞内域对BHV-1从三叉神经节传导至神经末梢的顺行轴突运输起关键作用。HSV gE的胞外域突变株gE-277不能从神经元向上皮细胞正常扩散[49]，缺失gE后，病毒从上皮细胞向神经元逆向转运过程也存在缺陷[50]。HSV-2缺失了gE的124—495位氨基酸，病毒无法从小鼠视网膜神经元扩散到大脑胞核中，也无法从上皮细胞向神经元传递[51]。说明gE同时影响HSV的顺向和逆向轴突转运。
gE/gI可以调节神经细胞内驱动蛋白KIF1A与US9蛋白之间的相互作用，促进病毒的轴突转运、在神经元的最终组装和向邻近细胞的传递[52-53]。gE和US9双缺失的HSV-1在神经元细胞质中无法正常组装，未包被和部分包被的核衣壳大量无序排列，累积在细胞质中，病毒粒子不能分选到轴突，导致病毒顺行轴突转运减少，无法转运到轴突末端扩散到邻近细胞[54-55]。仅缺失US9的HSV-1不仅可以经过视神经、感染视网膜扩散到大脑，还可以从脊椎侧翼扩散至脊髓；而gE和gI双缺失的病毒没有顺行传导，可能是因为gE/gI的胞外域可以介导病毒从胞外向上皮细胞传播，而US9没有胞外域结构[4]。缺失US9的PRV在相邻的非神经元细胞中的数量减少了104~105，而缺失gE仅减少了102~ 103，US9对于PRV的神经顺行运输和神经元的成熟组装更为重要[56-58]。
以上研究说明不同的α疱疹病毒gE/gI在轴突转运中发挥着重要的作用，gE/gI和US9协同促进轴突转运和病毒在神经元的成熟释放。
5 展 望疱疹病毒是危害人和动物的一类重要病原，研究其毒力基因有助于探究其发病机制，寻找防治病毒的有效途径。gE是重要的毒力基因，对病毒的致病性及毒力强弱有重要的作用。近年来，我国出现了高毒性、高致死性PRV变异毒株，在基因序列中gE、gI、TK等多个免疫和毒力基因发生了不同的插入、缺失、碱基置换突变[59-63]，其中PRV变异毒株ZJ01可以导致14或80日龄猪全部死亡，gE序列中有2个氨基酸的插入[64]。Dong等[65]将ZJ01株和亲本病毒LA株的gE和gI基因置换构建成两个重组病毒rZJ01-LA/gEI和rLA-ZJ01/gEI，发现rZJ01-LA/gEI和ZJ01都对仔猪有较高的毒力，但仔猪在感染rZJ01-LA /gEI后存活时间延长，rLA-ZJ01/gEI比LA对猪的致病率更高，说明gE基因的变化是导致PRV毒株近几年毒力增强的部分原因。但目前关于gE如何影响病毒粒子在细胞间传播的分子机制等研究还很匮乏，例如gE在次级囊膜包被和胞间传递的作用，以及gE蛋白与其他蛋白之间的关系。阐明这些机制这将有助于研究病毒病理学机制，研发出阻止细胞间传播的药物。
潜伏感染是α疱疹病毒的生存策略，其潜伏于三叉神经使动物或人在患病后终生带毒。在潜伏感染激活后，病毒在感染神经元的神经传导对于病毒在宿主体内和宿主之间的复制和传播是必不可少的。然而，目前关于神经潜伏感染的相关机制研究并不十分透彻，应该以gE基因诱导病毒侵袭神经系统并建立潜伏感染为研究的突破点，更深入地探索gE在神经细胞内和突触间传导的作用机制，探索相关的组织神经传导通路，并针对病毒的神经传导过程研发安全高效的疫苗和靶向药物。
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