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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.

Original publication

DOI

10.1016/j.immuni.2005.09.016

Type

Journal article

Journal

Immunity

Publication Date

11/2005

Volume

23

Pages

465 - 478

Keywords

Fibroblasts, Gene Expression Regulation, Humans, Interferons, Interleukin-1 Receptor-Associated Kinases, Phosphotransferases (Alcohol Group Acceptor), Poly I-C, Signal Transduction, Toll-Like Receptor 7, Toll-Like Receptor 8, Toll-Like Receptor 9, Toll-Like Receptors, Virus Diseases, Viruses