Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter.
Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter.
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移植诱导的小鼠巨细胞病毒立即早期基因表达的再激活与将 NF-κB 和 AP-1 招募到主要立即早期启动子相关。
DOI：
10.1099/jgv.0.000407
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Hummel,Mary
中科院分区：
文献类型：
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作者：
Liu,Xue-Feng;Jie,Chunfa;Zhang,Zheng;Yan,Shixian;Wang,Jiao-Jing;Wang,Xueqiong;Kurian,Sunil;Salomon,DanielR;Abecassis,Michael;Hummel,Mary
潜伏的人类巨细胞病毒的重新激活是器官移植的一个重要的感染性并发症，目前的治疗方法针对的是一旦潜伏病毒重新激活就进行病毒复制。激活病毒基因表达以响应移植的具体分子途径还不是很清楚。我们的研究旨在确定这些因素，目的是开发防止移植受者转录重新激活的新疗法。小鼠巨细胞病毒(MCMV)是研究CMV体内潜伏和再激活的有价值的模型。我们先前证明，将巨细胞病毒潜伏感染的肾脏移植到异基因受者体内，可以在48 小时内诱导立即早期(IE)基因表达的重新激活和主要立即早期启动子(MIEP)的表观遗传重编程。我们假设这些事件是通过激活信号通路来介导的，这些信号通路导致转录因子与MIEP结合，包括AP-1和NF-κB。我们展示了移植诱导AP-1和NF-κB转录因子家族的几个成员的快速激活，我们证明了典型的NF-κB(AP-1的联合成分)和核小体重塑复合体被招募到移植后的MIEP中。受体血浆蛋白质组学分析和肾组织转录组分析确定了5种细胞外配体，包括肿瘤坏死因子、IL-1β、IL-18、CD40L和IL-6，以及与IE基因表达重新激活有关的3条细胞内信号通路。识别介导这些信号通路激活的因素可能最终导致防止CMV及其后遗症重新激活的新疗法。
Reactivation of latent human cytomegalovirus is a significant infectious complication of organ transplantation and current therapies target viral replication once reactivation of latent virus has already occurred. The specific molecular pathways that activate viral gene expression in response to transplantation are not well understood. Our studies aim to identify these factors, with the goal of developing novel therapies that prevent transcriptional reactivation in transplant recipients. Murine cytomegalovirus (MCMV) is a valuable model for studying latency and reactivation of CMVin vivo. We previously demonstrated that transplantation of MCMV-latently infected kidneys into allogeneic recipients induces reactivation of immediate early (IE) gene expression and epigenetic reprogramming of the major immediate early promoter (MIEP) within 48 h. We hypothesize that these events are mediated by activation of signalling pathways that lead to binding of transcription factors to the MIEP, including AP-1 and NF-κB. Here we show that transplantation induces rapid activation of several members of the AP-1 and NF-κB transcription factor family and we demonstrate that canonical NF-κB (p65/p50), the junD component of AP-1, and nucleosome remodelling complexes are recruited to the MIEP following transplantation. Proteomic analysis of recipient plasma and transcriptome analysis of kidney RNA identified five extracellular ligands, including TNF, IL-1β, IL-18, CD40L and IL-6, and three intracellular signalling pathways associated with reactivation of IE gene expression. Identification of the factors that mediate activation of these signalling pathways may eventually lead to new therapies to prevent reactivation of CMV and its sequelae.