Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7

Abstract

Interferon (IFN) genes are among the earliest transcriptional responses to virus infection of mammalian cells.Although the regulation of the IFNβ gene has been well characterized, the induction of the large family of IFNα genes has remained obscure. We report that the IFNα genes can be divided into two groups: an immediate-early response gene (IFNα4) which is induced rapidly and without the need for ongoing protein synthesis; and a set of genes that display delayed induction, consisting of at least IFNα2, 5, 6 and 8, which are induced more slowly and require cellular protein synthesis. One protein that must be synthesized for induction of the delayed gene set is IFN itself, presumably IFNα4 or IFNβ, which stimulates the Jak-Stat pathway through the IFN receptor, resulting in activation of the transcription factor interferonstimulated gene factor 3 (ISGF3). Among the IFNstimulated genes induced through this positive feedback loop is the IFN regulatory factor (IRF) protein, IRF7. Induction of IRF7 protein in response to IFN and its subsequent activation by phosphorylation in response to virus-specific signals, involving two C-terminal serine residues, are required for induction of the delayed IFNα gene set.

Fish virus-induced interferon exerts antiviral function through Stat1 pathway

“…Combined with a recent report that three zebrafish IFNs can directly induce the expression of themselves (LopezMunoz et al, 2009), this result suggested that fish IFN genes belong to ISGs group. In mammals, IFN␤ is an early phase IFN and can prime the expression of later phase IFN genes other than itself (Deonarain et al, 2000;Marie et al, 1998;Sato et al, 2000), and IFN␣ cannot be induced by itself (Ank et al, 2006). In contrast, type III IFNs are induced directly by type I IFNs and also themselves (Ank et al, 2008;Ank et al, 2006;Osterlund et al, 2007).…”

“…In mammals, activation of IRF3 is sufficient for the expression of early phase IFNs and in turn, the produced early phase IFNs are required for the expression of later phase IFN genes. In the latter case, IRF7 is necessary but, prior to its action, it has to be synthesized through the IFN␤-activated Stat1 pathway (Marie et al, 1998;Sato et al, 2000). IRF3 and IRF7 seem to play similar roles in regulation of type III IFNs (Ank et al, 2008).…”

IRF-3-dependent and augmented target genes during viral infection

“…The expression of type I IFN genes is tightly regulated, and IRF-3 is known to be involved in induction of IFN-b and IFN-a4 in response to virus. 9,25 Induction of IFN-a5 was previously described to be dependent on the IRF-7 transcription factor induced by IFN. 25 Our analysis now identifies IFN-a5 as an IRF-3-dependent direct response gene.…”

“…9,25 Induction of IFN-a5 was previously described to be dependent on the IRF-7 transcription factor induced by IFN. 25 Our analysis now identifies IFN-a5 as an IRF-3-dependent direct response gene. The IFNs are secreted from infected cells and thereby disseminate immune response signals to other cells of the body.…”

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

“…Furthermore, the kinetics of IRF in response to poly I:C may be limiting the longevity of any effects on type I IFN expression. Marie and colleagues compared the magnitude and kinetics of IFN secretion 37. Infection of WT embryo fibroblasts with Newcastle disease virus (NDV) or RNA resulted in the rapid production of high levels of IFN α with a peak at 6–8 h.…”