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. 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.