Jones Dallas, Blackmon Anna, Neff C Preston, Palmer Brent E, Gilden Don, Badani Hussain, Nagel Maria A
Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
Department of Medicine, Division of Allergy and Clinical Immunology, University of Colorado School of Medicine, Aurora, Colorado, USA.
J Virol. 2016 Nov 14;90(23):10527-10534. doi: 10.1128/JVI.01546-16. Print 2016 Dec 1.
Varicella-zoster virus (VZV) vasculopathy produces stroke, giant cell arteritis, and granulomatous aortitis, and it develops after virus reactivates from ganglia and spreads transaxonally to arterial adventitia, resulting in persistent inflammation and pathological vascular remodeling. The mechanism(s) by which inflammatory cells persist in VZV-infected arteries is unknown; however, virus-induced dysregulation of programmed death ligand 1 (PD-L1) may play a role. Specifically, PD-L1 can be expressed on virtually all nucleated cells and suppresses the immune system by interacting with the programmed cell death protein receptor 1, found exclusively on immune cells; thus, downregulation of PD-L1 may promote inflammation, as seen in some autoimmune diseases. Both flow cytometry and immunofluorescence analyses to test whether VZV infection of adventitial cells downregulates PD-L1 showed decreased PD-L1 expression in VZV-infected compared to mock-infected human brain vascular adventitial fibroblasts (HBVAFs), perineural cells (HPNCs), and fetal lung fibroblasts (HFLs) at 72 h postinfection. Quantitative RT-PCR analyses showed no change in PD-L1 transcript levels between mock- and VZV-infected cells, indicating a posttranscriptional mechanism for VZV-mediated downregulation of PD-L1. Flow cytometry analyses showed decreased major histocompatibility complex class I (MHC-I) expression in VZV-infected cells and adjacent uninfected cells compared to mock-infected cells. These data suggest that reduced PD-L1 expression in VZV-infected adventitial cells contribute to persistent vascular inflammation observed in virus-infected arteries from patients with VZV vasculopathy, while downregulation of MHC-I prevents viral clearance.
Here, we provide the first demonstration that VZV downregulates PD-L1 expression in infected HBVAFs, HPNCs, and HFLs, which, together with the noted VZV-mediated downregulation of MHC-I, might foster persistent inflammation in vessels, leading to pathological vascular remodeling during VZV vasculopathy and persistent inflammation in infected lungs to promote subsequent infection of T cells and hematogenous virus spread. Identification of a potential mechanism by which persistent inflammation in the absence of effective viral clearance occurs in VZV vasculopathy and VZV infection of the lung is a step toward targeted therapy of VZV-induced disease.
水痘带状疱疹病毒（VZV）血管病可导致中风、巨细胞动脉炎和肉芽肿性主动脉炎，它在病毒从神经节重新激活并经轴突扩散至动脉外膜后发生，导致持续性炎症和病理性血管重塑。炎症细胞在VZV感染的动脉中持续存在的机制尚不清楚；然而，病毒诱导的程序性死亡配体1（PD-L1）失调可能起作用。具体而言，PD-L1几乎可在所有有核细胞上表达，并通过与仅在免疫细胞上发现的程序性细胞死亡蛋白受体1相互作用来抑制免疫系统；因此，PD-L1的下调可能会促进炎症，如在一些自身免疫性疾病中所见。流式细胞术和免疫荧光分析均用于检测外膜细胞的VZV感染是否会下调PD-L1，结果显示，与模拟感染的人脑血管外膜成纤维细胞（HBVAFs）、神经周细胞（HPNCs）和胎儿肺成纤维细胞（HFLs）相比，VZV感染的细胞在感染后72小时PD-L1表达降低。定量逆转录聚合酶链反应分析显示，模拟感染和VZV感染的细胞之间PD-L1转录水平没有变化，表明VZV介导的PD-L1下调是一种转录后机制。流式细胞术分析显示，与模拟感染的细胞相比，VZV感染的细胞及其相邻未感染的细胞中主要组织相容性复合体I类（MHC-I）表达降低。这些数据表明，VZV感染的外膜细胞中PD-L1表达降低有助于在VZV血管病患者的病毒感染动脉中观察到的持续性血管炎症，而MHC-I的下调则阻止病毒清除。
在此，我们首次证明VZV下调感染的HBVAFs、HPNCs和HFLs中的PD-L1表达，这与VZV介导的MHC-I下调一起，可能会促进血管中的持续性炎症，导致VZV血管病期间的病理性血管重塑以及感染肺部的持续性炎症，从而促进T细胞的后续感染和血行性病毒传播。确定VZV血管病和肺部VZV感染在缺乏有效病毒清除的情况下发生持续性炎症的潜在机制是朝着VZV诱导疾病的靶向治疗迈出的一步。
