The ETS transcription factor ELF1 regulates a critical, broadly antiviral program distinct from the type I interferon response. The ETS transcription factor ELF1 regulates a critical, broadly antiviral program distinct from the type I interferon response

Induction of vast transcriptional programs is a central event of innate host responses to viral infections. Here we report a unique transcriptional program with potent antiviral activity, driven by E74-like ETS transcription factor 1 (ELF1). Using high-content microscopy to quantify viral infection over time, we found that ELF1 inhibits eight diverse RNA and DNA viruses uniquely at multi-cycle replication. Elf1 deficiency results in enhanced susceptibility to influenza A virus infections in mice. ELF1 does not feed-forward to induce interferons, and ELF1’s antiviral effect is not abolished by the absence of STAT1 or by inhibition of JAK phosphorylation. Accordingly, comparative expression analyses by RNAseq revealed that the ELF1 transcriptional program is distinct from interferon signatures. Thus, ELF1 provides an additional layer of the innate host response, independent from the action of type I interferons. Overall design: A549 cells were not-transduced or transduced with empty vector, ELF1-WT, or ELF1-R8A mutant. Indicated cultures were stimulated with interferon beta for 6 hours or 48 hours. All samples were harvested simultaneously and analyzed by RNA-Seq.

大规模转录程序的诱导是宿主针对病毒感染的先天免疫应答的核心环节。本研究报道了一种由E74样ETS转录因子1（E74-like ETS transcription factor 1，ELF1）驱动的、具备强效抗病毒活性的独特转录程序。
我们利用高内涵显微镜（high-content microscopy）实时定量监测病毒感染的动态过程，发现ELF1可特异性在多轮复制阶段抑制八种不同的RNA病毒与DNA病毒。
在小鼠体内，Elf1基因缺陷会导致宿主对甲型流感病毒感染的易感性显著升高。
ELF1并不会通过前馈通路诱导干扰素产生，且其抗病毒效应不会因信号转导与转录激活因子1（STAT1）缺失或贾纳斯激酶（JAK）磷酸化抑制而被消除。
据此，通过RNA测序（RNA-seq）开展的比较转录组分析显示，ELF1调控的转录程序与干扰素特征信号存在显著差异。
综上，ELF1构成了宿主先天免疫应答的另一层调控通路，其功能不依赖于I型干扰素的作用。
实验整体设计：将A549细胞分为未转导组、空载体转导组、ELF1野生型（ELF1-WT）转导组以及ELF1-R8A突变体转导组；部分培养体系经β干扰素刺激6小时或48小时。所有样本同步收集后通过RNA-seq进行转录组分析。