Pyogenic Bacterial Infections in Humans with IRAK-4 Deficiency

• Published in: Science (American Association for the Advancement of Science) Vol. 299; no. 5615; pp. 2076 - 2079
• Main Authors: Picard, Capucine, Puel, Anne, Bonnet, Marion, Ku, Cheng-Lung, Bustamante, Jacinta, Yang, Kun, Soudais, Claire, Dupuis, Stéphanie, Feinberg, Jacqueline, Fieschi, Claire, Elbim, Carole, Hitchcock, Remi, Lammas, David, Davies, Graham, Al-Ghonaium, Abdulaziz, Al-Rayes, Hassan, Al-Jumaah, Sulaiman, Al-Hajjar, Sami, Al-Mohsen, Ibrahim Zaid, Frayha, Husn H., Rucker, Rajivi, Hawn, Thomas R., Aderem, Alan, Tufenkeji, Haysam, Haraguchi, Soichi, Day, Noorbibi K., Good, Robert A., Gougerot-Pocidalo, Marie-Anne, Ozinsky, Adrian, Casanova, Jean-Laurent
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 28.03.2003; The American Association for the Advancement of Science
• Subjects: Alleles; B lymphocytes; Bacteria; Biological and medical sciences; Blood cells; Child; Children; Coding; Codon, Terminator; Control Groups; Cultured cells; Cytokines - secretion; Diseases; Drosophila Proteins; Enzyme linked immunosorbent assay; Feedback (Response); Female; Fibroblasts; Fibroblasts - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genetics of the immune response; Gram-positive bacterial infections; Humans; Immunity; Immunity (Physiology); Immunobiology; Infections; Interleukin-1; Interleukin-1 Receptor-Associated Kinases; Interleukins - immunology; Interleukins - secretion; Ligands; Lipopolysaccharides - immunology; Male; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - immunology; Membrane Glycoproteins - metabolism; Microorganisms; Molecular biology; Monocytes - immunology; Mutation; Neutrophils - immunology; Patients; Pediatric diseases; Pedigree; Phosphotransferases (Alcohol Group Acceptor) - deficiency; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Pneumococcal Infections - immunology; Pneumococcal Infections - metabolism; Prevention; Protein Structure, Tertiary; Receptors; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - immunology; Receptors, Cell Surface - metabolism; Receptors, Interleukin - immunology; Receptors, Interleukin-1 - chemistry; Signal Transduction; Staphylococcal Infections - immunology; Staphylococcal Infections - metabolism; Toll-Like Receptors; Tumor Necrosis Factor-alpha - immunology; Western blotting; Saudi Arabia; United Kingdom; France; United States; Human; Enzyme; Transferases; Immunity; Streptococcus pneumoniae; Infection; Pyogenic; Streptococcaceae; Signal transduction; Protein kinase; Interleukin 1; Bacteriosis; Bacteria; Micrococcales; Micrococcaceae; Mutation; Child; Staphylococcus aureus; Toll-like receptor
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1081902

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 κB 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.