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

• DOI: 10.1016/j.immuni.2005.09.016
• Publication Date: 2005-11-16T12:24:39Z
• Authors: Kun Yang; Anne Puel; Shenying Zhang; Céline Eidenschenk; Cheng-Lung Ku; Armanda Casrouge; Capucine Picard; Horst von Bernuth; Brigitte Senechal; Sabine Plancoulaine; Sami Al-Hajjar; Abdulaziz Al-Ghon...; László Maródi; Donald Davidson; David Speert; Chaim Roifman; Ben-Zion Garty; Adrian Ozinsky; Franck J. Barrat; Robert L. Coffman; Richard L. Miller; Xiaoxia Li; Pierre Lebon; Carlos Rodriguez-...; Helen Chapel; Frédéric Geissmann; Emmanuelle Jouanguy; Jean-Laurent Casa...
• Keywords: Immunology; Article; 03 medical and health sciences; 0302 clinical medicine; Immunology and Allergy; Humans; 3205 Medicina interna; Toll-Like Receptors; Immunity; Fibroblasts; 3. Good health; Phosphotransferases (Alcohol Group Acceptor); Infectious Diseases; Interleukin-1 Receptor-Associated Kinases; Poly I-C; Gene Expression Regulation; Toll-Like Receptor 7; Toll-Like Receptor 8; Virus Diseases; Toll-Like Receptor 9; Viruses; Interferons; 32 Ciencias médicas; Signal Transduction

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.