Figure 6.
Inborn errors of TLR3TFN-α/β-mediated immunity in childhood herpes simplex encephalitis (HSE): schematic representation of the production of and response to IFN-α/β and IFN-λ in herpes simplex virus 1 (HSV-1) immunity. HSV-1 produces viral double-stranded RNA (dsRNA) during its replication. TLR3 is a transmembrane receptor of dsRNA in the endoplasmic reticulum (ER) and endosome in most cells. In central nervous system (CNS) cells, the recognition of dsRNA by TLR3 induces activation of the IRF3 and NF-κB pathways via TRIF, leading to the production of IFN-α/β and/or IFN-λ. TLR3, UNC-93B, TRIF, TRAF3, TBK1, and NEMO deficiencies are associated with impaired IFN-α/β and/or IFN-λ production, particularly during HSV-1 infection. The binding of IFN-α/β or IFN-λ to its receptor induces the phosphorylation of JAK1 and TYK2, activating the signal transduction proteins STAT1, STAT2, and IRF9. This complex is translocated, as a heterotrimer, to the nucleus, where it acts as a transcriptional activator, binding to specific DNA response elements in the promoter region of IFN-inducible genes. STAT1 deficiencies are associated with impaired IFN-α, -β, and -λ responses. Proteins for which genetic mutations have been identified and associated with susceptibility to isolated HSE are shown in blue. Proteins for which genetic mutations have been identified and associated with susceptibility to mycobacterial, bacterial, and viral diseases (including HSE) are shown in green. Proteins for which genetic mutations have been identified but not directly associated with susceptibility to HSE are shown in red.