Epigenetic suppression of interferon lambda receptor expression leads to enhanced HuNoV replication in vitro
Epigenetic suppression of interferon lambda receptor expression leads to enhanced HuNoV replication in vitro
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干扰素 lambda 受体表达的表观遗传抑制导致 HuNoV 体外复制增强
DOI：
10.1101/523282
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Arthur S
中科院分区：
文献类型：
--
作者：
Arthur S
人诺如病毒（HuNoV）是全球急性胃肠炎的主要原因，但目前尚无治疗方法。在这里，我们利用人诺如病毒复制子在上皮人胃肿瘤（HGT）细胞，以确定参与促进或抑制HuNoV复制的宿主因子。我们观察到，与亲本HGT细胞相比，携带复制子的HGT细胞（HGT-治愈）的IFN-治愈群体复制转染的HuNoV RNA的能力增强，表明HGT-治愈细胞中的差异基因表达创造了有利于病毒RNA复制的环境。微阵列分析用于鉴定与亲本HGT细胞相比在HGT-NV和HGT-治愈中差异调节的基因。我们发现，IFN λ受体α（IFNLR 1）的表达在HGT-NV和HGT治愈的细胞中高度降低。3种细胞系均通过诱导干扰素刺激基因（ISG）对外源性IFN-β产生应答，而HGT-NV和HGT-cured对外源性IFN-λ无应答。用5-氮杂-2 '-脱氧胞苷抑制DNA甲基转移酶活性部分地重新激活HGT-NV和IFN治愈的细胞中的IFNLR 1表达，表明宿主适应通过表观遗传重编程发生。与该观察结果一致，IFN-λ受体α的异位表达拯救了HGT-NV和HGT治愈的细胞对IFN-λ的应答。我们得出结论，III型IFN在体外抑制HuNoV复制中是重要的，并且IFNLR 1的丧失增强了HuNoV的复制。据我们所知，这项研究首次揭示了干扰素λ受体的表观遗传重编程作为长期RNA病毒复制过程中细胞适应的新机制，并表明干扰素λ信号传导的内源性水平能够控制人诺如病毒复制。
Human norovirus (HuNoV) is the main cause of acute gastroenteritis worldwide yet no therapeutics are currently available. Here, we utilize a human norovirus replicon in epithelial human gastric tumor (HGT) cells to identify host factors involved in promoting or inhibiting HuNoV replication. We observed that an IFN-cured population of replicon-harboring HGT cells (HGT-cured) was enhanced in their ability to replicate transfected HuNoV RNA compared to parental HGT cells, suggesting that differential gene expression in HGT-cured cells created an environment favouring the replication of viral RNA. Microarray analysis was used to identify genes differentially regulated in HGT-NV and HGT-cured compared to parental HGT cells. We found that the IFN lambda receptor alpha (IFNLR1) expression was highly reduced in HGT-NV and HGT-cured cells. All three cell lines responded to exogenous IFN-β by inducing interferon stimulated genes (ISGs), however, HGT-NV and HGT-cured failed to respond to exogenous IFN-λ. Inhibition of DNA methyltransferase activity with 5-aza-2’-deoxycytidine partially reactivated IFNLR1 expression in HGT-NV and IFN-cured cells suggesting that host adaptation occurred via epigenetic reprogramming. In line with this observation, ectopic expression of the IFN-λ receptor alpha rescued HGT-NV and HGT-cured cells response to IFN-λ. We conclude that type III IFN is important in inhibiting HuNoV replication in vitro and that the loss of IFNLR1 enhances replication of HuNoV. To the best of our knowledge, this study unravels for the first time epigenetic reprograming of the interferon lambda receptor as a new mechanism of cellular adaptation during long-term RNA virus replication and shows that an endogenous level of interferon lambda signalling is able to control human norovirus replication.
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影响因子：
7.3
作者：
Pervolaraki K;Stanifer ML;Münchau S;Renn LA;Albrecht D;Kurzhals S;Senís E;Grimm D;Schröder-Braunstein J;Rabin RL;Boulant S
通讯作者：
Boulant S
诺如病毒和医学参加了美国儿童的胃肠炎。
DOI：
10.1056/nejmsa1206589
发表时间：
2013-03-21
期刊：
The New England journal of medicine
影响因子：
--
作者：
Payne DC;Vinjé J;Szilagyi PG;Edwards KM;Staat MA;Weinberg GA;Hall CB;Chappell J;Bernstein DI;Curns AT;Wikswo M;Shirley SH;Hall AJ;Lopman B;Parashar UD
通讯作者：
Parashar UD
影响因子：
4.4
作者：
Ank, Nina;Iversen, Marie B.;Paludan, Soren R.
通讯作者：
Paludan, Soren R.
影响因子：
7.6
作者：
Rocha-Pereira, Joana;Jacobs, Sophie;Neyts, Johan
通讯作者：
Neyts, Johan
影响因子：
30.5
作者：
Sheppard, P;Kindsvogel, W;Klucher, KM
通讯作者：
Klucher, KM