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 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.

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Affiliated Institutions

• King Faisal Specialist Hospital & Research Centre SA
• Hôpital Necker-Enfants Malades FR
• Great Ormond Street Hospital GB
• Institute for Systems Biology US
• Inserm FR
• Immune Regulation (United Kingdom) GB
• University of South Florida St. Petersburg US
• Human Genetic of Infectious Diseases FR
• University College London GB
• University of Birmingham GB

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