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Pyogenic Bacterial Infections in Humans with IRAK-4 Deficiency
Capucine Picard,1Anne Puel,1Marion Bonnet,1Cheng-Lung Ku,1Jacinta Bustamante,1Kun Yang,1Claire Soudais,1Stéphanie Dupuis,1Jacqueline Feinberg,1Claire Fieschi,1Carole Elbim,2Remi Hitchcock,3David Lammas,4Graham Davies,5Abdulaziz Al-Ghonaium,6Hassan Al-Rayes,6Sulaiman Al-Jumaah,6Sami Al-Hajjar,6Ibrahim Zaid Al-Mohsen,6Husn H. Frayha,6Rajivi Rucker,3Thomas R. Hawn,7Alan Aderem,7Haysam Tufenkeji,6Soichi Haraguchi,3Noorbibi K. Day,3Robert A. Good,3Marie-Anne Gougerot-Pocidalo,2Adrian Ozinsky,7Jean-Laurent Casanova18*
Members of the Toll-like receptor (TLR) and
interleukin-1 receptor (IL-1R) superfamily share an intracytoplasmic
Toll-IL-1receptor (TIR) domain, which mediates recruitment of the
interleukin-1receptor-associated kinase (IRAK) complex via
TIR-containing adaptermolecules. We describe three unrelated children
with inheritedIRAK-4 deficiency. Their blood and fibroblast cells did
not activatenuclear factor B and mitogen-activated protein kinase
(MAPK)and failed to induce downstream cytokines in response to any ofthe known ligands of TIR-bearing receptors. The otherwise healthychildren developed infections caused by pyogenic bacteria. Thesefindings suggest that, in humans, the TIR-IRAK signaling pathwayis
crucial for protective immunity against specific bacteria butis
redundant against most other microorganisms.
1 Laboratoire de Génétique Humaine
des Maladies Infectieuses, Université René Descartes-INSERM
U550, Faculté Necker, 156 rue de Vaugirard, 75015 Paris, France.
2 Service d'Immunologie Cellulaire, Laboratoire
d'Hématologie et d'Immunologie, INSERM U294, Faculté
Xavier Bichat, 75018 Paris, France.
3 Department of
Pediatrics, Division of Allergy and Immunology, University of South
Florida and All Children's Hospital, St. Petersburg, FL 33701, USA.
4 MRC Center for Immune Regulation, The Medical
School, University of Birmingham, Birmingham B15 2TT, UK.
5 Infectious Diseases Unit, Great Ormond Street
Hospital for Children, London WC1N 3JH, UK.
6 Department of Pediatrics, King Faisal Specialist
Hospital and Research Center, Riyadh 11211, Kingdom of Saudi Arabia.
7 Institute for Systems Biology, 1441 North 34th
Street, Seattle, WA 98103, USA.
8 Unité
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:
casanova{at}necker.fr
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B 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.
