Herpes simplex virus encephalitis of childhood: inborn errors of central nervous system cell-intrinsic immunity

Abstract

Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Over the last 15 years, human genetic and immunological studies have provided proof-of-principle that childhood HSE can result from inborn errors of central nervous system (CNS)-specific, cell-intrinsic immunity to HSV-1. HSE-causing mutations of eight genes disrupt known (TLR3-dependent IFN-α/β immunity) and novel (dependent on DBR1 or snoRNA31) antiviral mechanisms. Monogenic inborn errors confer susceptibility to forebrain (TLR3-IFN or snoRNA31) or brainstem (DBR1) HSE. Most of these disorders display incomplete clinical penetrance, with the possible exception of DBR1 deficiency. They account for a small, but non-negligible proportion of cases (about 7%). These findings pave the way for the gradual definition of the genetic and immunological architecture of childhood HSE, with both biological and clinical implications.

Figure 1.. Inborn errors of immunity conferring predisposition to childhood HSE

Monogenic inborn errors of the TLR3-IFN circuit or snoRNA31 confer susceptibility to forebrain HSE, whereas inborn errors of DBR1 underlie brainstem HSE. TLR3 signaling is initiated by the recognition of dsRNA, inducing activation of the IRF3 and NF-κB pathways via TRIF, leading to the production of IFN-α/β and/or IFN-λ. Mutations of six TLR3 signaling pathway genes (TLR3, UNC93B1, TRIF, TRAF3, TBK1, and IRF3, highlighted in blue) have been found in patients with forebrain HSE. Mutations of other two genes of the TLR3-IFN circuit (NEMO, STAT1, in orange) have been found in patients suffering from HSE together with mycobacterial disease. Impaired TLR3-dependent, IFN-mediated cortical neuron- and oligodendrocyte-autonomous anti-HSV-1 immunity may underlie the pathogenesis of HSE in patients with TLR3 pathway gene defects. SnoRNA31 deficiency impairs cortical neuron-intrinsic immunity to HSV-1. DBR1 is a protein that shuttles between the cell nucleus and cytoplasm. DBR1 deficiency leads to defective RNA lariat metabolism and impaired cell-intrinsic immunity to HSV-1, despite normal cellular responses to stimulation with TLR3 or IFN-α/β. The fine molecular and cellular mechanisms by which snoRNA31 or DBR1 (in violet) deficiencies cause forebrain and brainstem HSE, respectively, remain to be dissected in detail.