Doceul Virginie, Chauveau Emilie, Lara Estelle, Bréard Emmanuel, Sailleau Corinne, Zientara Stéphan, Vitour Damien
ANSES, INRA, ENVA, UPEC, UMR 1161 Virology, Maisons-Alfort, France.
ANSES, INRA, ENVA, UPEC, UMR 1161 Virology, Maisons-Alfort, France
J Virol. 2014 Sep;88(18):10792-802. doi: 10.1128/JVI.01235-14. Epub 2014 Jul 9.
Bluetongue virus (BTV) is a double-stranded RNA (dsRNA) virus that causes an economically important disease in ruminants. BTV infection is a strong inducer of type I interferon (IFN-I) in multiple cell types. It has been shown recently that BTV and, more specifically, the nonstructural protein NS3 of BTV are able to modulate the IFN-I synthesis pathway. However, nothing is known about the ability of BTV to counteract IFN-I signaling. Here, we investigated the effect of BTV on the IFN-I response pathway and, more particularly, the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription protein (STAT) signaling pathway. We found that BTV infection triggered the expression of IFN-stimulated genes (ISGs) in A549 cells. However, when BTV-infected cells were stimulated with external IFN-I, we showed that activation of the IFN-stimulated response element (ISRE) promoter and expression of ISGs were inhibited. We found that this inhibition involved two different mechanisms that were dependent on the time of infection. After overnight infection, BTV blocked specifically the phosphorylation and nuclear translocation of STAT1. This inhibition correlated with the redistribution of STAT1 in regions adjacent to the nucleus. At a later time point of infection, BTV was found to interfere with the activation of other key components of the JAK/STAT pathway and to induce the downregulation of JAK1 and TYK2 protein expression. Overall, our study indicates for the first time that BTV is able to interfere with the JAK/STAT pathway to modulate the IFN-I response.
Bluetongue virus (BTV) causes a severe disease in ruminants and has an important impact on the livestock economy in areas of endemicity such as Africa. The emergence of strains, such as serotype 8 in Europe in 2006, can lead to important economic losses due to commercial restrictions and prophylactic measures. It has been known for many years that BTV is a strong inducer of type I interferon (IFN-I) in vitro and in vivo in multiple cell types. However, the ability of BTV to interact with the IFN-I system remains unclear. Here, we report that BTV is able to modulate the IFN-I response by interfering with the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription protein (STAT) signaling pathway. These findings contribute to knowledge of how BTV infection interferes with the host's innate immune response and becomes pathogenic. This will also be important for the design of efficacious vaccine candidates.
蓝舌病毒（BTV）是一种双链RNA（dsRNA）病毒，可在反刍动物中引起具有经济重要性的疾病。BTV感染是多种细胞类型中I型干扰素（IFN-I）的强诱导剂。最近的研究表明，BTV，更具体地说是BTV的非结构蛋白NS3，能够调节IFN-I合成途径。然而，关于BTV对抗IFN-I信号传导的能力尚不清楚。在这里，我们研究了BTV对IFN-I反应途径的影响，更具体地说是对Janus酪氨酸激酶（JAK）/信号转导和转录激活蛋白（STAT）信号通路的影响。我们发现BTV感染触发了A549细胞中干扰素刺激基因（ISG）的表达。然而，当用外源性IFN-I刺激BTV感染的细胞时，我们发现干扰素刺激反应元件（ISRE）启动子的激活和ISG的表达受到抑制。我们发现这种抑制涉及两种不同的机制，这两种机制取决于感染时间。过夜感染后，BTV特异性阻断STAT1的磷酸化和核转位。这种抑制与STAT1在细胞核附近区域的重新分布相关。在感染的后期时间点，发现BTV会干扰JAK/STAT途径其他关键成分的激活，并诱导JAK1和TYK2蛋白表达的下调。总体而言，我们的研究首次表明BTV能够干扰JAK/STAT途径以调节IFN-I反应。
蓝舌病毒（BTV）在反刍动物中引起严重疾病，并对非洲等流行地区的畜牧业经济产生重要影响。2006年欧洲出现的血清型8等毒株的出现，由于商业限制和预防措施，可能导致重大经济损失。多年来已知BTV在体外和体内的多种细胞类型中都是I型干扰素（IFN-I）的强诱导剂。然而，BTV与IFN-I系统相互作用的能力仍不清楚。在这里，我们报告BTV能够通过干扰Janus酪氨酸激酶（JAK）/信号转导和转录激活蛋白（STAT）信号通路来调节IFN-I反应。这些发现有助于了解BTV感染如何干扰宿主的先天免疫反应并致病。这对于设计有效的候选疫苗也很重要。
