Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia.
Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia.
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DOI：
10.1371/journal.ppat.1003773
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Wack A
中科院分区：
文献类型：
--
作者：
Crotta S;Davidson S;Mahlakoiv T;Desmet CJ;Buckwalter MR;Albert ML;Staeheli P;Wack A
干扰素（ifn）是一组具有良好抗病毒功能的细胞因子。它们可以被病毒感染诱导，分泌并与相同或邻近细胞上的特定受体结合，以激活数百种具有抗病毒功能的IFN刺激基因（isg）的表达。I型IFN已经被发现了半个多世纪。然而，最近，III型IFN （IFNλ, IL-28/29）被证明发挥类似的作用，并且在上皮表面特别重要。本研究表明，甲型流感病毒的主要靶点气道上皮在感染后产生IFN I和IFN III，并且两者的诱导依赖于RIG-I/MAVS通路。虽然IRF3通常被认为是启动IFN转录和所谓的“启动环”所需的转录因子，但我们发现IRF3缺乏对IFN表达的影响很小。相反，缺乏IRF7显著降低了IFN的产生，只有IRF3−/−IRF7−/−双缺乏才能完全消除IFN的产生。流感感染的转录应答在很大程度上依赖于IFN，因为在I型和III型IFN （IFNAR1−/−IL-28Rα−/−）缺乏受体的上皮细胞中，它被减少到少数上调基因。野生型上皮和缺乏I型IFN受体或III型IFN受体的上皮在对病毒的反应中表现出相似的转录谱，表明没有任何诱导基因选择性地仅依赖于一种IFN系统。在嵌合小鼠中，间质室中缺乏IFN I和III信号显著增加了对流感感染的易感性。综上所述，病毒感染气道上皮通过RIG-I/MAVS/IRF7依赖通路诱导I型和III型ifn，它们驱动两个完全重叠和冗余的扩增环上调isg并保护免受流感感染。细胞对病毒感染的反应取决于干扰素（ifn），干扰素是一组细胞因子，可激活数百种基因的表达，帮助控制感染细胞内的病毒复制。I型IFN于1957年被发现，而III型IFN （IFNλ, IL-28/29）是最近才被发现的，并因其在丙型肝炎病毒应答中的作用而闻名。气道上皮是流感病毒的主要靶点，我们研究了感染如何诱导IFN以及哪种IFN在上皮抗流感反应中最重要。我们发现，感染的上皮细胞通过细胞质RIG-I/MAVS识别系统检测病毒，导致转录因子IRF7的激活，随后诱导I型和III型ifn的产生。所有随后的细胞对感染的反应都依赖于ifn的产生和分泌，因为在缺乏I型和III型ifn受体的上皮中，反应丢失。最后，基因诱导在单受体缺陷和野生型细胞中是无法区分的，这表明两个IFN系统在上皮中是完全冗余的。因此，气道上皮的流感感染通过RIG-I/MAVS/IRF7依赖通路诱导I型和III型ifn，它们驱动两个重叠和冗余的扩增环上调抗病毒基因。
Interferons (IFNs) are a group of cytokines with a well-established antiviral function. They can be induced by viral infection, are secreted and bind to specific receptors on the same or neighbouring cells to activate the expression of hundreds of IFN stimulated genes (ISGs) with antiviral function. Type I IFN has been known for more than half a century. However, more recently, type III IFN (IFNλ, IL-28/29) was shown to play a similar role and to be particularly important at epithelial surfaces. Here we show that airway epithelia, the primary target of influenza A virus, produce both IFN I and III upon infection, and that induction of both depends on the RIG-I/MAVS pathway. While IRF3 is generally regarded as the transcription factor required for initiation of IFN transcription and the so-called “priming loop”, we find that IRF3 deficiency has little impact on IFN expression. In contrast, lack of IRF7 reduced IFN production significantly, and only IRF3−/−IRF7−/− double deficiency completely abolished it. The transcriptional response to influenza infection was largely dependent on IFNs, as it was reduced to a few upregulated genes in epithelia lacking receptors for both type I and III IFN (IFNAR1−/−IL-28Rα−/−). Wild-type epithelia and epithelia deficient in either the type I IFN receptor or the type III IFN receptor exhibit similar transcriptional profiles in response to virus, indicating that none of the induced genes depends selectively on only one IFN system. In chimeric mice, the lack of both IFN I and III signalling in the stromal compartment alone significantly increased the susceptibility to influenza infection. In conclusion, virus infection of airway epithelia induces, via a RIG-I/MAVS/IRF7 dependent pathway, both type I and III IFNs which drive two completely overlapping and redundant amplification loops to upregulate ISGs and protect from influenza infection. The response of cells to virus infection depends on Interferons (IFNs), a group of cytokines which activate the expression of hundreds of genes that help control viral replication inside infected cells. While type I IFN was discovered in 1957, type III IFN (IFNλ, IL-28/29) was characterized recently and is known for its role in the response to hepatitis C virus. Airway epithelia are the primary target of influenza virus, and we studied how infection induces IFNs and which IFN is most important for the epithelial anti-influenza response. We found that infected epithelia detect virus through the cytoplasmic RIG-I/MAVS recognition system, leading to activation of the transcription factor IRF7 and subsequent induction of both type I and III IFNs. All ensuing cellular responses to infection are dependent on the production and secretion of IFNs, as responses are lost in epithelia lacking receptors for both type I and III IFNs. Finally, gene induction is indistinguishable in single receptor-deficient and wild-type cells, indicating that the two IFN systems are completely redundant in epithelia. Thus, influenza infection of airway epithelia induces, via a RIG-I/MAVS/IRF7 dependent pathway, both type I and III IFNs which drive two overlapping and redundant amplification loops to upregulate antiviral genes.
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