GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141

Abstract

Herpes simplex virus 1 (HSV-1) infects several billion people worldwide and can cause life-threatening herpes simplex encephalitis (HSE) in some patients. Monogenic defects in components of the type I interferon system have been identified in patients with HSE, emphasizing the role of inborn errors of immunity underlying HSE pathogenesis. Here, we identify compound heterozygous loss-of-function mutations in the gene GTF3A encoding for transcription factor IIIA (TFIIIA), a component of the RNA polymerase III complex, in a patient with common variable immunodeficiency and HSE. Patient fibroblasts and GTF3A gene–edited cells displayed impaired HSV-1–induced innate immune responses and enhanced HSV-1 replication. Chromatin immunoprecipitation sequencing analysis identified the 5 S ribosomal RNA pseudogene 141 ( RNA5SP141 ), an endogenous ligand of the RNA sensor RIG-I, as a transcriptional target of TFIIIA. GTF3A mutant cells exhibited diminished RNA5SP141 expression and abrogated RIG-I activation upon HSV-1 infection. Our work unveils a crucial role for TFIIIA in transcriptional regulation of a cellular RIG-I agonist and shows that GTF3A genetic defects lead to impaired cell-intrinsic anti–HSV-1 responses and can predispose to HSE.

The immunobiology of herpes simplex virus encephalitis and post-viral autoimmunity

“… 70 A recent study described a child afflicted by HSE who was found to harbour a compound heterozygous variant in the GTF3A gene, which encodes for the transcription factor IIIA (TFIIIA); a moonlighting protein with protective properties against HSV through production of the RIG-I ligand, RNA5SP141. 71 This patient (and his sister) exhibited a diminished IFN-I response to HSV-1 in isolated patient fibroblasts and GTF3A gene-edited cells.…”

Inborn Errors of Immunity Predisposing to Herpes Simplex Virus Infections of the Central Nervous System

“…Recently, Naesens and colleagues reported a case of HSE in a patient who was compound heterozygous for variants in GTF3A [ 75 ]. This gene encodes the transcription factor IIIA (TFIIIA), which is essential for POL III-mediated transcription of 5S rRNA species.…”

“…In a mechanism analogous to the guard theory of plant immunity [ 94 ], RNA 5S ribosomal 141 is released from its sequestration and can now induce the RIG-I-mediated activation of IFN-I [ 33 ] ( Figure 2 A,B). Interestingly, both the reported patient and his sister (who also harbored both GTF3A variants but did not experience HSE) had decreased IFN-I responses to HSV-1, and this could be rescued by reconstitution with WT GTF3A [ 75 ]. Both siblings also had a CVID-like phenotype [ 75 ], and, although rare, HSE is not unheard of among CVID patients, as discussed below [ 95 ].…”

“…Interestingly, both the reported patient and his sister (who also harbored both GTF3A variants but did not experience HSE) had decreased IFN-I responses to HSV-1, and this could be rescued by reconstitution with WT GTF3A [ 75 ]. Both siblings also had a CVID-like phenotype [ 75 ], and, although rare, HSE is not unheard of among CVID patients, as discussed below [ 95 ]. It remains to be clarified if the biallelic GTF3A variants disturb B cell function as well and whether the HSE phenotype manifests exclusively in the context of disturbed B cell function (primary or secondary).…”

“…Advances in our basic understanding of immunology is crucial to the discovery of novel immunodeficiencies. Without the discovery of RNA5SP141 -mediated RIG-I activation, the connection between GTF3A and HSE is unlikely to have been made [ 33 , 75 ]. However, the opposite is also true, as evidenced by the body of literature, testifying to the ability of the discoveries of novel IEI in humans to teach us as yet uncovered principles of antiviral immunity in humans.…”