Chikungunya Virus Nonstructural Protein 2 Inhibits Type I/II Interferon-Stimulated JAK-STAT Signaling
Chikungunya Virus Nonstructural Protein 2 Inhibits Type I/II Interferon-Stimulated JAK-STAT Signaling
复制标题
DOI：
10.1128/jvi.00949-10
复制
发表时间：
2010-10-01
影响因子：
5.4
通讯作者：
Pijlman, Gorben P.
中科院分区：
文献类型：
--
作者：
Fros, Jelke J.;Liu, Wen Jun;Pijlman, Gorben P.
基孔肯雅病毒(CHIKV)是一种通过蚊子传播的新型人类病原体。与其他甲型病毒一样，CHIKV复制会导致宿主全面关闭，导致哺乳动物细胞产生严重的细胞病变，并抑制感染细胞对干扰素的反应能力。然而，最近的研究表明，甲型病毒可能有额外的机制来绕过宿主的抗病毒干扰素反应。在这里，我们表明，一旦建立了RNA复制，CHIKV的复制就抵抗了干扰素的抑制，并且CHIKV通过阻止干扰素诱导的基因表达来主动抑制抗病毒的干扰素反应。CHIKV感染和CHIKV复制子RNA复制都有效地阻断了I型和II型干扰素诱导的哺乳动物细胞中STAT1的磷酸化和/或核转位。单个CHIKV非结构蛋白(NSP)的表达表明，NSP2是干扰素诱导的JAK-STAT信号的有效抑制因子。此外，CHIKV-nsP2(P718S)和Sindbis病毒(SINV)-nsP2(P726S)突变使甲型病毒复制子非细胞病变显著减少了JAK-STAT抑制。CHIKV对干扰素信号的这种非宿主关闭的抑制可能在病毒的发病机制中起着重要作用。
Chikungunya virus (CHIKV) is an emerging human pathogen transmitted by mosquitoes. Like that of other alphaviruses, CHIKV replication causes general host shutoff, leading to severe cytopathicity in mammalian cells, and inhibits the ability of infected cells to respond to interferon (IFN). Recent research, however, suggests that alphaviruses may have additional mechanisms to circumvent the host's antiviral IFN response. Here we show that CHIKV replication is resistant to inhibition by interferon once RNA replication has been established and that CHIKV actively suppresses the antiviral IFN response by preventing IFN-induced gene expression. Both CHIKV infection and CHIKV replicon RNA replication efficiently blocked STAT1 phosphorylation and/or nuclear translocation in mammalian cells induced by either type I or type II IFN. Expression of individual CHIKV nonstructural proteins (nsPs) showed that nsP2 was a potent inhibitor of IFN-induced JAK-STAT signaling. In addition, mutations in CHIKV-nsP2 (P718S) and Sindbis virus (SINV)-nsP2 (P726S) that render alphavirus replicons noncytopathic significantly reduced JAK-STAT inhibition. This host shutoff-independent inhibition of IFN signaling by CHIKV is likely to have an important role in viral pathogenesis.