Pyogenic bacterial infections in humans with IRAK-4 deficiency.
Members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) superfamily share an intracytoplasmic Toll-IL-1 receptor (TIR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. We describe three unrelated children with inherited IRAK-4 deficiency. Their blood and fibroblast cells did not activate nuclear factor kappaB and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors. The otherwise healthy children developed infections caused by pyogenic bacteria. These findings suggest that, in humans, the TIR-IRAK signaling pathway is crucial for protective immunity against specific bacteria but is redundant against most other microorganisms.
Picard
Capucine
C
Laboratoire de Génétique Humaine des Maladies Infectieuses, Université René Descartes-INSERM U550, Faculté Necker, 156 rue de Vaugirard, 75015 Paris, France.
Puel
Anne
A
Bonnet
Marion
M
Ku
Cheng-Lung
CL
Bustamante
Jacinta
J
Yang
Kun
K
Soudais
Claire
C
Dupuis
Stéphanie
S
Feinberg
Jacqueline
J
Fieschi
Claire
C
Elbim
Carole
C
Hitchcock
Remi
R
Lammas
David
D
Davies
Graham
G
Al-Ghonaium
Abdulaziz
A
Al-Rayes
Hassan
H
Al-Jumaah
Sulaiman
S
Al-Hajjar
Sami
S
Al-Mohsen
Ibrahim Zaid
IZ
Frayha
Husn H
HH
Rucker
Rajivi
R
Hawn
Thomas R
TR
Aderem
Alan
A
Tufenkeji
Haysam
H
Haraguchi
Soichi
S
Day
Noorbibi K
NK
Good
Robert A
RA
Gougerot-Pocidalo
Marie-Anne
MA
Ozinsky
Adrian
A
Casanova
Jean-Laurent
JL
D000483:Alleles; D002648:Child; D018388:Codon, Terminator; D016207:Cytokines / Q000378:metabolism; D029721:Drosophila Proteins; D005260:Female; D005347:Fibroblasts / Q000276:immunology; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology; D009154:Mutation; D009504:Neutrophils / Q000276:immunology; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D011008:Pneumococcal Infections / Q000276:immunology* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D018123:Receptors, Interleukin / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000737:chemistry; D015398:Signal Transduction; D013203:Staphylococcal Infections / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D018388:Codon, Terminator; D016207:Cytokines; D029721:Drosophila Proteins; D007378:Interleukins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases