Previous TLR-signaling deficiencies linked to disease in humans include the following: TLR3 deficiency as a cause of herpes simplex encephalitis, MyD88-IRAK4 deficiency in pyogenic infections, MDA5 deficiency underlying severe HRV infection, inherited IRF7 and IRF9 deficiencies associated with severe influenza pneumonitis, and TIRAP deficiency as a cause of staphylococcal disease [29–33]. Here, IRAK4 is linked to herpes simplex encephalitis.