title: Pyogenic bacterial infections in humans with IRAK-4 deficiency.
abstract: 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.
authors.affiliation: Laboratoire de Génétique Humaine des Maladies Infectieuses, Université René Descartes-INSERM U550, Faculté Necker, 156 rue de Vaugirard, 75015 Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Marion
authors.initials: M
authors.lastname: Bonnet
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Ku
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Claire
authors.initials: C
authors.lastname: Soudais
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Dupuis
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Feinberg
authors.forename: Claire
authors.initials: C
authors.lastname: Fieschi
authors.forename: Carole
authors.initials: C
authors.lastname: Elbim
authors.forename: Remi
authors.initials: R
authors.lastname: Hitchcock
authors.forename: David
authors.initials: D
authors.lastname: Lammas
authors.forename: Graham
authors.initials: G
authors.lastname: Davies
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Al-Ghonaium
authors.forename: Hassan
authors.initials: H
authors.lastname: Al-Rayes
authors.forename: Sulaiman
authors.initials: S
authors.lastname: Al-Jumaah
authors.forename: Sami
authors.initials: S
authors.lastname: Al-Hajjar
authors.forename: Ibrahim Zaid
authors.initials: IZ
authors.lastname: Al-Mohsen
authors.forename: Husn H
authors.initials: HH
authors.lastname: Frayha
authors.forename: Rajivi
authors.initials: R
authors.lastname: Rucker
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hawn
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
authors.forename: Haysam
authors.initials: H
authors.lastname: Tufenkeji
authors.forename: Soichi
authors.initials: S
authors.lastname: Haraguchi
authors.forename: Noorbibi K
authors.initials: NK
authors.lastname: Day
authors.forename: Robert A
authors.initials: RA
authors.lastname: Good
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Gougerot-Pocidalo
authors.forename: Adrian
authors.initials: A
authors.lastname: Ozinsky
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: 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
chemical_list: 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