Abstract
Induction of vast transcriptional programs is a central event of innate host responses to viral infections. Here we report a transcriptional program with potent antiviral activity, driven by E74-like ETS transcription factor 1 (ELF1). Using microscopy to quantify viral infection over time, we found that ELF1 inhibits eight diverse RNA and DNA viruses after 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 RNA-seq 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.
Highlights
The innate immune system provides a first line of defense against viral infections, achieving its remarkable potency through the establishment of complex transcriptional programs
We show that ELF1 regulates expression of a previously unidentified set of genes, which results in a potent antiviral state both in vitro and in vivo
To establish ELF1 as a component of the antiviral immune response, we determined its expression in different cell lines, primary cell culture systems, and a mouse model, upon interferon treatment, stimulation with pathogen-associated molecular patterns (PAMPs), or viral infection (Fig 1 and S1 Fig)
Summary
The innate immune system provides a first line of defense against viral infections, achieving its remarkable potency through the establishment of complex transcriptional programs. Upon interferon signal transduction, phosphorylated STAT1/2 and IRF9 form the interferon-stimulated gene factor 3 (ISGF3) complex, which localizes to interferon-sensitive response elements (ISREs) and initiates the transcription of ISGs [7,8]. IRF1, itself an ISG, has broad and potent antiviral activity against a wide variety of RNA and DNA viruses [3,4]. This activity appears to be mediated through direct transcriptional initiation of a subset of ISGs, even in the absence of interferon or intact interferon signaling [4]. IRF7 was the first innate transcription factor functionally associated with enhanced susceptibility to influenza virus infections in patients [13]
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