Pyogenic Bacterial Infections in Humans with IRAK-4 Deficiency

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

¹Laboratoire de Génétique Humaine des Maladies Infectieuses, Université René Descartes-INSERM U550, Faculté Necker, 156 rue de Vaugirard, 75015 Paris, France. ²Service d'Immunologie Cellulaire, Laboratoire d'Hématologie et d'Immunologie, INSERM U294, Faculté Xavier Bichat, 75018 Paris, France. ³Department of Pediatrics, Division of Allergy and Immunology, University of South Florida and All Children's Hospital, St. Petersburg, FL 33701, USA. ⁴MRC Center for Immune Regulation, The Medical School, University of Birmingham, Birmingham B15 2TT, UK. ⁵Infectious Diseases Unit, Great Ormond Street Hospital for Children, London WC1N 3JH, UK. ⁶Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Kingdom of Saudi Arabia. ⁷Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103, USA. ⁸Unité d'Immunologie et d'Hématologie Pédiatriques, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France.

*To whom correspondence should be addressed. E-mail: [email protected]

Supporting Online Material: www.sciencemag.org/cgi/content/full/1081902/DC1; SOM Text; Materials and Methods; References

24 December 2002; accepted 27 February 2003

Published online 13 March 2003; 10.1126/science.1081902

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Science 299(5615):p 2076-2079, March 28, 2003.

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.