Hantavirus regulation of type I interferon responses.
Hantavirus regulation of type I interferon responses.
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DOI：
10.1155/2012/524024
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发表时间：
2012
影响因子：
2.2
通讯作者：
Mackow ER
中科院分区：
文献类型：
--
作者：
Matthys V;Mackow ER
汉坦病毒主要感染人内皮细胞（EC）并引起两种高度致命的人类疾病。早期加入I型干扰素（IFN）的EC阻断汉他病毒复制，因此汉他病毒是致病性的，他们需要防止早期干扰素诱导。PHV复制在人EC中被阻断，但在IFN缺陷型VeroE 6细胞中不受抑制，与此一致，用PHV感染EC导致IFNβ和一系列干扰素刺激基因（ISG）的早期诱导。相反，ANDV、HTNV、NY-1V和TULV汉坦病毒抑制早期ISG诱导并在人EC内成功复制。汉坦病毒对IFN应答的抑制作用归因于几种病毒蛋白，包括Gn蛋白质胞质尾（Gn-T）的调节。Gn-T干扰IRF 3激活和IFN诱导所需的STING-TBK 1-TRAF 3复合物的形成，而PHV Gn-T不能改变该复合物或调节IFN诱导。这些研究结果表明，干扰干扰早期干扰素诱导是必要的汉他病毒复制在人类内皮细胞，并建议，汉他病毒的致病性需要额外的决定因素。Gn-Ts破坏IFN信号传导的机制可能揭示潜在的治疗干预措施，并提出减毒汉坦病毒的蛋白质靶点。
Hantaviruses primarily infect human endothelial cells (ECs) and cause two highly lethal human diseases. Early addition of Type I interferon (IFN) to ECs blocks hantavirus replication and thus for hantaviruses to be pathogenic they need to prevent early interferon induction. PHV replication is blocked in human ECs, but not inhibited in IFN deficient VeroE6 cells and consistent with this, infecting ECs with PHV results in the early induction of IFNβ and an array of interferon stimulated genes (ISGs). In contrast, ANDV, HTNV, NY-1V and TULV hantaviruses, inhibit early ISG induction and successfully replicate within human ECs. Hantavirus inhibition of IFN responses has been attributed to several viral proteins including regulation by the Gn proteins cytoplasmic tail (Gn-T). The Gn-T interferes with the formation of STING-TBK1-TRAF3 complexes required for IRF3 activation and IFN induction, while the PHV Gn-T fails to alter this complex or regulate IFN induction. These findings indicate that interfering with early IFN induction is necessary for hantaviruses to replicate in human ECs, and suggest that additional determinants are required for hantaviruses to be pathogenic. The mechanism by which Gn-Ts disrupt IFN signaling is likely to reveal potential therapeutic interventions and suggest protein targets for attenuating hantaviruses.