Induction of interferon-stimulated genes by IRF3 promotes replication of Toxoplasma gondii.
Induction of interferon-stimulated genes by IRF3 promotes replication of Toxoplasma gondii.
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DOI：
10.1371/journal.ppat.1004779
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发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Barik S
中科院分区：
文献类型：
--
作者：
Majumdar T;Chattopadhyay S;Ozhegov E;Dhar J;Goswami R;Sen GC;Barik S
固有免疫是抵御微生物侵害的第一道防线。转录因子IRF3是哺乳动物细胞针对许多微生物（尤其是病毒）产生固有免疫应答所必需的。在未受感染的细胞的细胞质中，IRF3处于无活性状态；在病毒感染时，它会被磷酸化，然后转移到细胞核，在那里它与抗病毒基因的启动子结合并诱导其表达。这类基因包括I型干扰素（IFNs）以及干扰素刺激基因（ISGs）。IRF3基因敲除的细胞会使许多病毒的复制增强，因此，相应的小鼠对病毒致病作用高度易感。在此，我们提供了IRF3具有意外的促微生物作用的证据：在IRF3基因敲除的细胞中，原生动物寄生虫刚地弓形虫的复制显著受损。在探究IRF3的转录活性对其促寄生虫功能是否重要时，我们发现由寄生虫激活的IRF3所诱导的ISGs确实是必需的，而I型干扰素并不重要。为了描绘在寄生虫感染时激活IRF3的信号通路，我们使用了基因改造的人和小鼠细胞。我们将这种促寄生虫信号通路称为PISA（寄生虫 - IRF3信号激活），它在不涉及Toll样受体或RIG - I样受体通路的情况下激活IRF3，从而排除了寄生虫来源的RNA种类在激活PISA中的作用。相反，PISA需要cGAS、STING、TBK1和IRF3的存在，这表明DNA触发的信号是必需的。为了评估我们体外研究结果的生理意义，用寄生虫感染IRF3基因敲除的小鼠，并测量它们的发病率和死亡率。与野生型小鼠不同，IRF3基因敲除的小鼠不支持寄生虫的复制，并且对其引起的发病具有抵抗力。我们的结果揭示了一个新的范例，即抗病毒宿主因子IRF3在细胞内具有促寄生虫的作用。
干扰素调节因子3（IRF3）是抗病毒基因（包括I型干扰素和干扰素刺激基因）表达所必需的转录因子。干扰素刺激基因的协同作用导致病毒生命周期的一个或多个步骤受到抑制。与IRF3众所周知的抗病毒功能相反，我们在此报告了IRF3在细胞和小鼠中支持原生动物寄生虫刚地弓形虫复制的意外的促寄生虫作用。IRF3缺陷型小鼠不支持刚地弓形虫的复制，因此，免受刚地弓形虫诱导的发病。IRF3新的促刚地弓形虫作用不依赖于I型干扰素，但需要其诱导效应干扰素刺激基因的转录功能。通过使用在IRF3激活通路的已知成分上有缺陷的细胞，我们描绘了促寄生虫信号通路的性质，我们将其命名为“PISA”。我们详细的遗传学和生物化学分析表明，PISA是由刚地弓形虫触发的细胞质cGAS/STING/TBK1依赖性通路激活的，该通路激活IRF3以诱导促寄生虫的干扰素刺激基因。
Innate immunity is the first line of defense against microbial insult. The transcription factor, IRF3, is needed by mammalian cells to mount innate immune responses against many microbes, especially viruses. IRF3 remains inactive in the cytoplasm of uninfected cells; upon virus infection, it gets phosphorylated and then translocates to the nucleus, where it binds to the promoters of antiviral genes and induces their expression. Such genes include type I interferons (IFNs) as well as Interferon Stimulated Genes (ISGs). IRF3-/- cells support enhanced replication of many viruses and therefore, the corresponding mice are highly susceptible to viral pathogenesis. Here, we provide evidence for an unexpected pro-microbial role of IRF3: the replication of the protozoan parasite, Toxoplasma gondii, was significantly impaired in IRF3-/- cells. In exploring whether the transcriptional activity of IRF3 was important for its pro-parasitic function, we found that ISGs induced by parasite-activated IRF3 were indeed essential, whereas type I interferons were not important. To delineate the signaling pathway that activates IRF3 in response to parasite infection, we used genetically modified human and mouse cells. The pro-parasitic signaling pathway, which we termed PISA (Parasite-IRF3 Signaling Activation), activated IRF3 without any involvement of the Toll-like receptor or RIG-I-like receptor pathways, thereby ruling out a role of parasite-derived RNA species in activating PISA. Instead, PISA needed the presence of cGAS, STING, TBK1 and IRF3, indicating the necessity of DNA-triggered signaling. To evaluate the physiological significance of our in vitro findings, IRF3-/- mice were challenged with parasite infection and their morbidity and mortality were measured. Unlike WT mice, the IRF3-/- mice did not support replication of the parasite and were resistant to pathogenesis caused by it. Our results revealed a new paradigm in which the antiviral host factor, IRF3, plays a cell-intrinsic pro-parasitic role. Interferon Regulatory Factor 3 (IRF3) is an essential transcription factor for the expression of antiviral genes, including type I IFNs and ISGs. The coordinated action of the ISGs leads to the inhibition of one or multiple steps of viral life cycle. In contrast to the well-known antiviral function of IRF3, we report here an unexpected pro-parasitic role of IRF3 in supporting the replication of the protozoan parasite, Toxoplasma gondii, in both cells and mice. The IRF3-deficient mice did not support T. gondii replication and, therefore, were protected from T. gondii-induced pathogenesis. The novel pro-Toxoplasma role of IRF3 was type I IFN-independent, but required its transcriptional function that induced the effector ISGs. Using cells deficient in known components of the IRF3 activation pathways, we have delineated the nature of the pro-parasitic signaling pathway, which we named ‘PISA’. Our detailed genetic and biochemical analyses revealed that PISA is activated by a T. gondii-triggered cytoplasmic cGAS/STING/TBK1-dependent pathway that activates IRF3 for the induction of the pro-parasitic ISGs.
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影响因子：
6.4
作者：
Chattopadhyay S;Fensterl V;Zhang Y;Veleeparambil M;Wetzel JL;Sen GC
通讯作者：
Sen GC
影响因子：
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作者：
Gissot, Mathieu;Choi, Sang-Woon;Kim, Kami
通讯作者：
Kim, Kami
影响因子：
3.7
作者：
Gaji RY;Huynh MH;Carruthers VB
通讯作者：
Carruthers VB
影响因子：
11.4
作者：
Chattopadhyay, Saurabh;Marques, Joao T.;Sen, Ganes C.
通讯作者：
Sen, Ganes C.
DOI：
10.1007/s100960050423
发表时间：
1999-12-01
影响因子：
4.5
作者：
Evans, R;Chatterton, JMW;Ho-Yen, DO
通讯作者：
Ho-Yen, DO