Nectin-1 Is an Entry Mediator for Varicella-Zoster Virus Infection of Human Neurons
Nectin-1 Is an Entry Mediator for Varicella-Zoster Virus Infection of Human Neurons
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Nectin-1 是人类神经元水痘带状疱疹病毒感染的进入介质
DOI：
10.1128/jvi.01227-21
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发表时间：
2021
影响因子：
5.4
通讯作者：
Venkatesan Arun
中科院分区：
文献类型：
--
作者：
Rajbhandari Labchan;Shukla Priya;Jagdish Balaji;Mandalla Abby;Li Qingxue;Ali Mir A.;Lee Hojae;Lee Gabsang;Sadaoka Tomohiko;Cohen Jeffrey I.;Venkatesan Arun
水痘-带状疱疹病毒（VZV）在初次感染后在神经元中保持终身潜伏，随后可被重新激活，导致带状疱疹或脑炎等严重神经系统症状。由于病毒具有严格的人向性，VZV神经发病机制的研究一直具有挑战性。虽然包括单纯疱疹病毒在内的其他疱疹病毒的神经元进入介质已经被确定，但对于VZV如何进入神经元知之甚少。在这里，我们利用基于人类干细胞的神经元模型来表征介导进入的细胞因子。通过感染细胞的转录谱分析，我们确定细胞粘附分子连接蛋白-1是VZV进入的候选介质。Nectin-1在神经元的细胞体和轴突高度表达。无论是敲除内源性nectin-1，还是与哺乳动物细胞中产生的可溶性nectin-1孵育，都能显著降低神经元的传染性。值得注意的是，在病毒感染期间添加可溶性nectin-1抑制了病毒的传染性，而在病毒感染后添加可溶性nectin-1对病毒的传染性没有影响。在抗VZV感染的细胞系中异位表达人nectin-1赋予感染易感性。总之，我们已经确定连接蛋白-1是VZV的神经元进入介质。evaricella -zoster病毒（VZV）引起水痘，在原发性感染期间获得进入神经元的途径，并终生存在，随后可被重新激活。再激活与带状疱疹和带状疱疹后神经痛以及严重的神经系统并发症有关，包括血管炎和脑炎。尽管水痘疫苗大大降低了与原发性感染相关的发病率和死亡率，但该疫苗不能预防神经元潜伏期的发展，接种疫苗的人群仍有再次激活的风险。此外，免疫功能低下的个体发生VZV再激活和相关并发症的风险更高。关于VZV如何进入神经元，我们所知甚少。在这里，我们确定了连接蛋白-1作为VZV在人类神经元中的进入介质。确定连接蛋白-1作为神经元VZV进入介质可能导致改善治疗和预防措施，以降低VZV相关的发病率和死亡率。
Varicella-zoster virus (VZV) maintains lifelong latency in neurons following initial infection and can subsequently be reactivated to result in herpes zoster or severe neurological manifestations such as encephalitis. Mechanisms of VZV neuropathogenesis have been challenging to study due to the strict human tropism of the virus. Although neuronal entry mediators of other herpesviruses, including herpes simplex virus, have been identified, little is known regarding how VZV enters neurons. Here, we utilize a human stem cell-based neuronal model to characterize cellular factors that mediate entry. Through transcriptional profiling of infected cells, we identify the cell adhesion molecule nectin-1 as a candidate mediator of VZV entry. Nectin-1 is highly expressed in the cell bodies and axons of neurons. Either knockdown of endogenous nectin-1 or incubation with soluble forms of nectin-1 produced in mammalian cells results in a marked decrease in infectivity of neurons. Notably, while addition of soluble nectin-1 during viral infection inhibits infectivity, addition after infection has no effect on infectivity. Ectopic expression of human nectin-1 in a cell line resistant to productive VZV infection confers susceptibility to infection. In summary, we have identified nectin-1 as a neuronal entry mediator of VZV.IMPORTANCEVaricella-zoster virus (VZV) causes chickenpox, gains access to neurons during primary infection where it resides lifelong, and can later be reactivated. Reactivation is associated with shingles and postherpetic neuralgia, as well as with severe neurologic complications, including vasculitis and encephalitis. Although the varicella vaccine substantially decreases morbidity and mortality associated with primary infection, the vaccine cannot prevent the development of neuronal latency, and vaccinated populations are still at risk for reactivation. Furthermore, immunocompromised individuals are at higher risk for VZV reactivation and associated complications. Little is known regarding how VZV enters neurons. Here, we identify nectin-1 as an entry mediator of VZV in human neurons. Identification of nectin-1 as a neuronal VZV entry mediator could lead to improved treatments and preventative measures to reduce VZV related morbidity and mortality.
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影响因子：
5.4
作者：
Zhang, Zhen;Rowe, Jenny;Zhu, Hua
通讯作者：
Zhu, Hua
影响因子：
3.7
作者：
Warner, MS;Geraghty, RJ;Spear, PG
通讯作者：
Spear, PG
单纯疱疹病毒受体 nectin-1 在与糖蛋白 D 反式相互作用后下调。
影响因子：
3.7
作者：
Stiles,KatieM;Milne,RichardSB;Cohen,GaryH;Eisenberg,RoselynJ;Krummenacher,Claude
通讯作者：
Krummenacher,Claude
影响因子：
15.9
作者：
Shukla, D;Spear, PG
通讯作者：
Spear, PG
影响因子：
56.9
作者：
Geraghty, RJ;Krummenacher, C;Spear, PG
通讯作者：
Spear, PG