Severe Invasive Infections Linked to Novel IRAK2 Immune Variants

In subjects with peculiar susceptibility to severe infections by common pyogenic bacteria, mutations of interleukin-1 receptor-associated kinase proteins (IRAK)1 and IRAK4 had been identified. The IRAK kinases function as downstream signal transductors following activation of pathogen recognition receptors. In 2 patients with sequential or repeated invasive infections: herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and Streptococcus pneumoniae bacteremia with candidemia respectively, novel mutations of IRAK2 were identified. These mutations compromised the capacity to ubiquinate (or functionally modify) the signal adaptor tumor necrosis factor receptor-associated factor 6 (TRAF6). The result is impairment of the cytokine TNF-alpha production. This susceptibility to a varied range of pathogens underlines a potential central role played by IRAK2 in mediating host defense in infectious diseases.