title: Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda 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.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes INSERM U550, Necker Medical School, 75015 Paris, France.
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Shenying
authors.initials: S
authors.lastname: Zhang
authors.forename: Céline
authors.initials: C
authors.lastname: Eidenschenk
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Ku
authors.forename: Armanda
authors.initials: A
authors.lastname: Casrouge
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Horst
authors.initials: H
authors.lastname: von Bernuth
authors.forename: Brigitte
authors.initials: B
authors.lastname: Senechal
authors.forename: Sabine
authors.initials: S
authors.lastname: Plancoulaine
authors.forename: Sami
authors.initials: S
authors.lastname: Al-Hajjar
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Al-Ghonaium
authors.forename: László
authors.initials: L
authors.lastname: Maródi
authors.forename: Donald
authors.initials: D
authors.lastname: Davidson
authors.forename: David
authors.initials: D
authors.lastname: Speert
authors.forename: Chaim
authors.initials: C
authors.lastname: Roifman
authors.forename: Ben-Zion
authors.initials: BZ
authors.lastname: Garty
authors.forename: Adrian
authors.initials: A
authors.lastname: Ozinsky
authors.forename: Franck J
authors.initials: FJ
authors.lastname: Barrat
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coffman
authors.forename: Richard L
authors.initials: RL
authors.lastname: Miller
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.forename: Pierre
authors.initials: P
authors.lastname: Lebon
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Gallego
authors.forename: Helen
authors.initials: H
authors.lastname: Chapel
authors.forename: Frédéric
authors.initials: F
authors.lastname: Geissmann
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D005347:Fibroblasts; D005786:Gene Expression Regulation; D006801:Humans; D007372:Interferons / Q000276:immunology* / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism*; D011070:Poly I-C / Q000276:immunology; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology* / Q000378:metabolism*; D014777:Virus Diseases / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014780:Viruses / Q000276:immunology*
chemical_list: C495348:TLR7 protein, human; C495349:TLR8 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D007372:Interferons; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases; D011070:Poly I-C