Other TLR Pathway Defects

Abstract

IRAK-4 and MyD88 deficiencies abolish the responses mediated by all Toll-like receptors (TLRs), except the responses to TLR-3 and some TLR-4-mediated responses, as well as IL-1 receptor-mediated responses. IRAK-4- and MyD88-deficient patients suffer from recurrent pyogenic bacterial infections, particularly invasive infections by Streptococcus pneumoniae and, to a lesser extent, Staphylococcus aureus and Pseudomonas aeruginosa. However, they are resistant to other microorganisms. IRAK-4 and MyD88 deficiencies are life-threatening in infancy and childhood. However, infections become rarer with age. A striking feature of IRAK-4 and MyD88 deficiencies is the low or delayed inflammatory responses in the course of infections. Patients with deficiencies of TLR3 immunity, due to mutations in UNC93B1, TLR3, TRIF, TRAF3, or TBK1, have a similar cellular phenotype consisting of impaired TLR3 signaling in fibroblasts, oligodendrocytes, and neurons. Patients suffer from herpes simplex virus-1 encephalitis, without detectable viral dissemination, but they remain normally resistant to other common viruses.