Pyogenic Bacterial Infections in Humans with IRAK-4 Deficiency

TLDR

Toll‑like and interleukin‑1 receptors signal through a shared TIR domain that recruits the IRAK kinase complex. The study reports three unrelated children with inherited IRAK‑4 deficiency. In these children, cells failed to activate NF‑κB and MAPK or produce cytokines in response to TIR‑bearing ligands, and they developed pyogenic bacterial infections, indicating that the TIR‑IRAK pathway is essential for defense against certain bacteria but dispensable for most other microbes.

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.