The pathogenic NY-1 hantavirus G1 cytoplasmic tail inhibits RIG-I- and TBK-1-directed interferon responses
The pathogenic NY-1 hantavirus G1 cytoplasmic tail inhibits RIG-I- and TBK-1-directed interferon responses
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DOI：
10.1128/jvi.00508-06
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发表时间：
2006-10-01
影响因子：
5.4
通讯作者：
Mackow, Erich R.
中科院分区：
文献类型：
--
作者：
Alff, Peter J.;Gavrilovskaya, Irina N.;Mackow, Erich R.
汉坦病毒引起两种具有显著血管通透性缺陷的疾病，肾综合征出血热和汉坦病毒肺综合征。所有的汉他病毒都感染人内皮细胞，尽管尚不清楚致病性和非致病性汉他病毒的区别。我们观察到显着差异的干扰素特异性转录反应之间的致病性和非致病性汉他病毒感染后1天，这表明汉他病毒的发病机制可能部分是由病毒调节细胞干扰素反应。与致病性NY-1病毒（NY-1V）和汉滩病毒（HTNV）不同，非致病性前景希尔病毒（PHV）在感染人内皮细胞后可诱导早期干扰素应答。我们确定PHV复制在人内皮细胞中被阻断，并且PHV（而不是NY-1V或HTNV）的RNA和蛋白质合成在感染后2至4天被抑制。加入β干扰素（IFN-β）抗体阻断干扰素介导的MxA诱导> 90%，证明汉坦病毒感染诱导内皮细胞分泌IFN-β。NY-1V和PHV共感染内皮细胞导致PHV诱导干扰素应答性MxA转录物减少60%，进一步表明NY-1V调节早期IFN应答的潜力。NY-1V G1胞质尾的表达受到干扰素刺激的反应元件或P-干扰素启动子的> 90% RIG-I和下游TBK-1定向转录的抑制，并呈剂量依赖性。相比之下，NY-1V核衣壳或PHV G1尾的表达对RIG-I或TBK-1指导的转录应答没有影响。此外，NY-1V和PHV GI尾均不抑制由组成型活性形式的干扰素调节因子3（IRF-3 5D）指导的转录应答，并且IRF-3是TBK-1磷酸化的直接靶标。这些发现表明，致病性NY-1V G1蛋白在TBK-1复合物水平调节IRF-3磷酸化上游的细胞IFN应答。这些发现进一步表明，GI胞质尾区含有一个毒力元件，它决定了汉坦病毒绕过先天性细胞免疫应答的能力，并描绘了致病性汉坦病毒在人内皮细胞内成功复制的机制。
Hantaviruses cause two diseases with prominent vascular permeability defects, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. All hantaviruses infect human endothelial cells, although it is unclear what differentiates pathogenic from nonpathogenic hantaviruses. We observed dramatic differences in interferon-specific transcriptional responses between pathogenic and nonpathogenic hantaviruses at I day postinfection, suggesting that hantavirus pathogenesis may in part be determined by viral regulation of cellular interferon responses. In contrast to pathogenic NY-1 virus (NY-1V) and Hantaan virus (HTNV), nonpathogenic Prospect Hill virus (PHV) elicits early interferon responses following infection of human endothelial cells. We determined that PHV replication is blocked in human endothelial cells and that RNA and protein synthesis by PHV, but not NY-1V or HTNV, is inhibited at 2 to 4 days postinfection. The addition of antibodies to beta interferon (IFN-beta) blocked interferon-directed MxA induction by > 90% and demonstrated that hantavirus infection induces the secretion of IFN-beta from endothelial cells. Coinfecting endothelial cells with NY-1V and PHV resulted in a 60% decrease in the induction of interferon-responsive MxA transcripts by PHV and further suggested the potential for NY-1V to regulate early IFN responses. Expression of the NY-1V G1 cytoplasmic tail inhibited by > 90% RIG-I- and downstream TBK-1-directed transcription from interferon-stimulated response elements or P-interferon promoters in a dose-dependent manner. In contrast, expression of the NY-1V nucleocapsid or PHV G1 tail had no effect on RIG-I- or TBK-1-directed transcriptional responses. Further, neither the NY-1V nor PHV GI tails inhibited transcriptional responses directed by a constitutively active form of interferon regulatory factor 3 (IRF-3 5D), and IRF-3 is a direct target of TBK-1 phosphorylation. These findings indicate that the pathogenic NY-1V G1 protein regulates cellular IFN responses upstream of IRF-3 phosphorylation at the level of the TBK-1 complex. These findings further suggest that the GI cytoplasmic tail contains a virulence element which determines the ability of hantaviruses to bypass innate cellular immune responses and delineates a mechanism for pathogenic hantaviruses to successfully replicate within human endothelial cells.