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.
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.
Yang
Kun
K
Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes INSERM U550, Necker Medical School, 75015 Paris, France.
Puel
Anne
A
Zhang
Shenying
S
Eidenschenk
Céline
C
Ku
Cheng-Lung
CL
Casrouge
Armanda
A
Picard
Capucine
C
von Bernuth
Horst
H
Senechal
Brigitte
B
Plancoulaine
Sabine
S
Al-Hajjar
Sami
S
Al-Ghonaium
Abdulaziz
A
Maródi
László
L
Davidson
Donald
D
Speert
David
D
Roifman
Chaim
C
Garty
Ben-Zion
BZ
Ozinsky
Adrian
A
Barrat
Franck J
FJ
Coffman
Robert L
RL
Miller
Richard L
RL
Li
Xiaoxia
X
Lebon
Pierre
P
Rodriguez-Gallego
Carlos
C
Chapel
Helen
H
Geissmann
Frédéric
F
Jouanguy
Emmanuelle
E
Casanova
Jean-Laurent
JL
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*
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