Human TLR-7-, -8-, and -9-Mediated Induction of IFN-α/β and -λ Is IRAK-4 Dependent and Redundant for Protective Immunity to Viruses

Abstract

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans.

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

“…40,41 Furthermore, interferon response genes such as MxA and 5 0 3 0 OAS are activated 2 and subjected to typical regulatory mechanisms. 11 Although the IFN-l receptor is widely expressed, 2,3 expression of the ligand is tightly controlled and takes place after viral infection 2,17 or stimulation via many of the Toll-like receptors (TLRs), 15 a process that is elevated by IFN-a. 42 Expression via stimulation of TLR 7, 8 and 9 IFN-k1 downregulates the human Th2 response WJ Jordan et al is absolutely dependent on IRAK-4 signaling, whereas IFN-l1 can be transcribed following stimulation of the cell via TLR 3 or 4 in an IRAK-4-independent manner.…”

“…42 Expression via stimulation of TLR 7, 8 and 9 IFN-k1 downregulates the human Th2 response WJ Jordan et al is absolutely dependent on IRAK-4 signaling, whereas IFN-l1 can be transcribed following stimulation of the cell via TLR 3 or 4 in an IRAK-4-independent manner. 15 This expression following cell triggering by such a wide range of TLR molecules, together with the broad range of STAT molecules activated, suggests a broader role for IFN-l1, particularly in the response to intracellular infection.…”

“…2 These observations, in conjunction with the induction of the IFN-l1/2/3 ligands by a range of viral infections and their ability to rescue virally infected cells, 2,3 have prompted a series of studies that have further investigated the antiviral properties of these cytokines. [8][9][10][11][12][13][14][15][16][17][18][19][20][21] However, the IFN-l ligands also induce the phosphorylation of STAT1, STAT3, STAT5 2,22 and STAT4. 23 Phosphorylation of STAT1, STAT3, STAT5 in particular, suggests more complex properties for the IFN-l ligand family; STAT3 is the signaling mechanism used by members of the IL-10 family (IL-10, IL-19, IL-20, etc.…”

Antiviral innate immunity pathways

“…However, in many other cell types, including cDCs, macrophages and fibroblasts, deletion of both MyD88 and TRIF, which abolishes all TLR signaling, has no effect on viral induction of IFNs [20]. Furthermore, although human patients deficient in IRAK4 are more 144 npg susceptible to bacterial infection, they have intact immune responses against viruses [21]. Therefore, there must be TLR-independent pathways that are highly effective in providing antiviral innate immunity.…”

Peripheral, but not central nervous system, type I interferon expression in mice in response to intranasal vesicular stomatitis virus infection

“…Host induction of type I IFNs during innate immune responses to antigens, viral, fungal, or bacterial challenge, to single-stranded RNA (ssRNA), double-stranded (dsRNA), and CpG in DNA has been associated with the triggering of a family of receptors termed Toll-like receptors (TLRs) for their sequence similarity to Toll, which was first identified in the fruit fly (reviewed in Boehme and Compton, 2004;Conzelmann, 2005;Kawai and Akira, 2005;Yang et al, 2005). Although many cell types are able to express some TLRs, research has indicated that the plasmacytoid dendritic cell (pDC) maintains a central role in the TLR-triggered IFN response (reviewed in Malmgaard, 2005).…”