Pyogenic bacterial infections in humans with IRAK-4 deficiency. (Reports)

Members of the Toll-like receptor (TIR) 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 KB 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.
The members of the mammalian Toll-like/ interleukin-1 receptor superfamily characteristically have a TIR domain (1). This superfamily contains two classes of membrane receptors: TLRs, seven of which recognize known ligands [...]