However, only IRF1, IRF3, IRF5 and IRF7 have been implicated as positive regulators of type I IFN transcription, and only IRF3 and IRF7 are designated as Epinephrine hydrochloride antiviral IRFs. Since their first discovery within the biological context of Epstein Barr virus latency, IRF7 was identified as the master regulator of the type I IFN-dependent immune response, and perhaps that of type III IFN as well. IRF7 is expressed only at low levels in most cells but is constitutively expressed in certain immune cells such as plasmacytoid dendritic cells which specialize in IFN production. Correspondingly, the tissue distribution of human IRF7 is restricted to immune tissues which contain large numbers of specialized immune cells including spleen, thymus and peripheral blood lymphocytes whereas non-immune tissues including the intestine and colon express almost undetectable levels of IRF7. Although IRF7 is expressed at low levels in most cell types, it is induced strongly by type I IFN mediated signaling in all cells. Interestingly, multiple fish species have been demonstrated to express IRF7 constitutively in all tissues including both immune and non-immune tissues. Viral sensing either by Toll like receptors or retinoic acid-inducible gene 1 -like receptors can result in the activation of IRF7 and subsequent induction of IFNs. All TLRs with the exception of TLR3 activate IRF7 through the adaptor protein, MyD88 through the MyD88-dependent pathway. MyD88 forms a complex with the kinases IRAK-4, IRAK-1 and TRAF-6. This complex binds directly to IRF7 leading to ubiquitination by TRAF-6 and phosphorylation by IRAK1 or IKK-1 and translocation from the cytosol to the nucleus where IRF7 binds to promoter elements inducing IFN production. TLR3 and TLR4 activate IRF7 through the MyD88-independent pathway through the adaptor E-64 molecule TRIF which forms a complex with TBK1, IKK-e and IRF7. In this case the phosphorylated IRF7 forms a homodimer or heterodimer with IRF3 and trans locates to the nucleus where it binds to the IFN promoter via its DNA-binding domain to induce type I or type III IFN. In IRF7 knockout mice, viral induced IFN production through the TLR3 pathway is greatly impaired.