Antagonism of Type I Interferon Responses by New World Hantaviruses
Antagonism of Type I Interferon Responses by New World Hantaviruses
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DOI：
10.1128/jvi.00916-10
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发表时间：
2010-11-01
影响因子：
5.4
通讯作者：
Feldmann, Heinz
中科院分区：
文献类型：
--
作者：
Levine, Jessica R.;Prescott, Joseph;Feldmann, Heinz
逃避干扰素（IFN）介导的抗病毒信号是致病性RNA病毒的常见防御策略。迄今为止，汉坦病毒对IFN拮抗作用的研究是有限的，并且只集中在众多已知汉坦病毒物种中的一个子集。宿主IFN应答有两个阶段，起始阶段导致α / β IFN的诱导（IFN- α / β），以及扩增阶段，此时IFN- α / β信号通过Jak/STAT通路，导致细胞抗病毒状态的建立。我们研究了这些关键宿主反应与新世界汉坦病毒之间的相互作用。我们观察到安第斯病毒(ANDV)-和Sin Nombre病毒(SNV)-感染A549和Huh7-TLR3细胞的延迟细胞反应。我们发现ifn - β的诱导被ANDV核衣壳蛋白（NP）和糖蛋白前体（GPC）的共表达抑制，并且被SNV GPC单独抑制。SNV的GPC和ANDV的NP或GPC也能抑制Jak/STAT信号的下游扩增。因此，ANDV和SNV编码的蛋白具有抑制ifn - β诱导和信号传导的潜力，SNV表现出更强的拮抗能力。在此，我们发现了一种以前未被识别的Jak/STAT信号抑制剂ANDV NP，并表明ANDV对IFN的拮抗作用依赖于糖蛋白和NP的表达，而糖蛋白似乎足以拮抗SNV。这些数据表明，汉坦病毒的IFN拮抗策略是非常不同的，甚至在具有相似疾病表型的物种之间也是如此，这可能有助于更好地阐明物种特异性发病机制。
Evasion of interferon (IFN)-mediated antiviral signaling is a common defense strategy for pathogenic RNA viruses. To date, research on IFN antagonism by hantaviruses is limited and has focused on only a subset of the numerous recognized hantavirus species. The host IFN response has two phases, an initiation phase, resulting in the induction of alpha/beta IFN (IFN-alpha/beta), and an amplification phase, whereby IFN-alpha/beta signals through the Jak/STAT pathway, resulting in the establishment of the cellular antiviral state. We examined interactions between these critical host responses and the New World hantaviruses. We observed delayed cellular responses in both Andes virus (ANDV)- and Sin Nombre virus (SNV)-infected A549 and Huh7-TLR3 cells. We found that IFN-beta induction is inhibited by coexpression of ANDV nucleocapsid protein (NP) and glycoprotein precursor (GPC) and is robustly inhibited by SNV GPC alone. Downstream amplification by Jak/STAT signaling is also inhibited by SNV GPC and by either NP or GPC of ANDV. Therefore, ANDV- and SNV-encoded proteins have the potential for inhibiting both IFN-beta induction and signaling, with SNV exhibiting the more potent antagonism ability. Herein we identify ANDV NP, a previously unrecognized inhibitor of Jak/STAT signaling, and show that IFN antagonism by ANDV relies on expression of both the glycoproteins and NP, whereas the glycoproteins appear to be sufficient for antagonism by SNV. These data suggest that IFN antagonism strategies by hantaviruses are quite variable, even between species with similar disease phenotypes, and may help to better elucidate species-specific pathogenesis.