The pUL37 tegument protein guides alpha-herpesvirus retrograde axonal transport to promote neuroinvasion.
The pUL37 tegument protein guides alpha-herpesvirus retrograde axonal transport to promote neuroinvasion.
复制标题
DOI：
10.1371/journal.ppat.1006741
复制
发表时间：
2017-12
期刊：
影响因子：
6.7
通讯作者：
Smith GA
中科院分区：
文献类型：
--
作者：
Richards AL;Sollars PJ;Pitts JD;Stults AM;Heldwein EE;Pickard GE;Smith GA
嗜神经性α-疱疹病毒的一个特点是感染在最初暴露在粘膜表面后传播到周围神经系统的感觉神经节和自主神经节。外周神经节是潜伏的病毒库，也是反复感染的来源，如疱疹(I型单纯疱疹病毒)和带状疱疹(水痘带状疱疹病毒)。然而，这些病毒例行公事地入侵神经系统的方式还没有完全了解。我们报告了一种内部的病毒粒子成分，pUL37被膜蛋白，其表面区是一个重要的神经侵袭效应因子。该区域的突变使得单纯疱疹病毒1型(HSV-1)和伪狂犬病病毒(PRV)在培养和动物中都不能通过逆行轴突运输传播到周围神经节。通过用延时荧光显微镜监测单个病毒颗粒的轴突运输，突变病毒被确定缺乏沿着微管的特征持续的细胞内衣壳运动，而微管通常将衣壳运送到神经体。与轴突运输缺陷一致，突变病毒没有到达外周神经节的潜伏点，并且是无毒的。尽管如此，病毒在外周组织和培养的上皮细胞系中的繁殖仍然很强劲。长期以来，人们一直在寻求选择性地消除对神经系统的逆行传递，以此作为开发针对这些无处不在、有时具有破坏性的病毒的疫苗的一种手段。为了支持这一潜力，我们发现HSV-1和PRV在pUL37的效应区发生突变，从而引发了针对随后的神经系统挑战和脑部疾病的有效疫苗接种。这些发现表明，疱疹病毒的逆行轴突运输是由病毒引导的机制发生的，该机制通过协调相对的微管发动机来有利于病毒持续逆行输送到外周神经节。选择性地消除这些病毒逆行轴突运输机制的能力将有助于哺乳动物神经系统的跨突触定位研究，并为人类和兽医嗜神经性疱疹病毒提供一种新的疫苗接种模式。阿尔法疱疹病毒的神经侵袭性成员包括人类(即单纯疱疹病毒I型；HSV-1)和兽医(即伪狂犬病病毒；PRV)病原体，这些病原体通常在没有明显组织损伤的情况下入侵具有免疫能力的宿主的外周神经系统。我们已经确定了这些病毒的一个基本的、保守的成分，它引导传入的病毒颗粒进入神经节。携带该蛋白效应区突变的病毒在接种的外围部位正常繁殖，但不能通过逆行轴突运输入侵神经系统，不能建立终身潜伏感染，并且是无毒的。这些特性定义了一种有希望的新型减毒活疫苗，可防止随后的神经系统入侵和脑炎疾病。
A hallmark property of the neurotropic alpha-herpesvirinae is the dissemination of infection to sensory and autonomic ganglia of the peripheral nervous system following an initial exposure at mucosal surfaces. The peripheral ganglia serve as the latent virus reservoir and the source of recurrent infections such as cold sores (herpes simplex virus type I) and shingles (varicella zoster virus). However, the means by which these viruses routinely invade the nervous system is not fully understood. We report that an internal virion component, the pUL37 tegument protein, has a surface region that is an essential neuroinvasion effector. Mutation of this region rendered herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV) incapable of spreading by retrograde axonal transport to peripheral ganglia both in culture and animals. By monitoring the axonal transport of individual viral particles by time-lapse fluorescence microscopy, the mutant viruses were determined to lack the characteristic sustained intracellular capsid motion along microtubules that normally traffics capsids to the neural soma. Consistent with the axonal transport deficit, the mutant viruses did not reach sites of latency in peripheral ganglia, and were avirulent. Despite this, viral propagation in peripheral tissues and in cultured epithelial cell lines remained robust. Selective elimination of retrograde delivery to the nervous system has long been sought after as a means to develop vaccines against these ubiquitous, and sometimes devastating viruses. In support of this potential, we find that HSV-1 and PRV mutated in the effector region of pUL37 evoked effective vaccination against subsequent nervous system challenges and encephalitic disease. These findings demonstrate that retrograde axonal transport of the herpesviruses occurs by a virus-directed mechanism that operates by coordinating opposing microtubule motors to favor sustained retrograde delivery of the virus to the peripheral ganglia. The ability to selectively eliminate the retrograde axonal transport mechanism from these viruses will be useful in trans-synaptic mapping studies of the mammalian nervous system, and affords a new vaccination paradigm for human and veterinary neurotropic herpesviruses. Neuroinvasive members of the alpha-herpesvirinae include human (i.e. herpes simplex virus type I; HSV-1) and veterinary (i.e. pseudorabies virus; PRV) pathogens that routinely invade the peripheral nervous system of an immunocompetent host in the absence of overt tissue damage. We have identified an essential, and conserved, component of these viruses that directs incoming viral particles into the neural ganglia. Viruses carrying mutations in this protein effector region propagate normally at peripheral sites of inoculation but fail to invade the nervous system by retrograde axonal transport, cannot establish life-long latent infections, and are avirulent. These properties define a promising new class of live-attenuated vaccines that protect from subsequent nervous system invasion and encephalitic disease.
登录
查看更多内容
腺病毒通过细胞质动力蛋白与病毒capsid己糖亚基的直接相互作用进行转运。
影响因子：
30.3
作者：
Bremner KH;Scherer J;Yi J;Vershinin M;Gross SP;Vallee RB
通讯作者：
Vallee RB
影响因子：
5.4
作者：
Coller, Kelly Elizabeth;Lee, Joy I-Hsuan;Smith, Gregory Allan
通讯作者：
Smith, Gregory Allan
影响因子：
5.4
作者：
Desai, PJ
通讯作者：
Desai, PJ
影响因子：
5.4
作者：
Copeland, Anna Maria;Newcomb, William W.;Brown, Jay C.
通讯作者：
Brown, Jay C.
DOI：
10.1107/s0907444910026582
发表时间：
2010-11-01
影响因子：
2.2
作者：
Afonine, Pavel V.;Mustyakimov, Marat;Adams, Paul D.
通讯作者：
Adams, Paul D.