Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency
Paul Bastard, … , Jean-Laurent Casanova, Shen-Ying Zhang
Paul Bastard, … , Jean-Laurent Casanova, Shen-Ying Zhang
Published September 22, 2020
Citation Information: J Clin Invest. 2021;131(1):e139980. https://doi.org/10.1172/JCI139980.
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Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

Abstract

Inborn errors of TLR3-dependent IFN-α/β– and IFN-λ–mediated immunity in the CNS can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/β and IFN-λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3′-UTR of the last exon of IFNAR1, who died of HSE at the age of 2 years. An older cousin died following vaccination against measles, mumps, and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe, viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient’s fibroblasts and EBV-B cells did not respond to IFN-α2b or IFN-β, in terms of STAT1, STAT2, and STAT3 phosphorylation or the genome-wide induction of IFN-stimulated genes. The patient’s fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-α2b or IFN-β. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This viral disease occurred in natural conditions, unlike those previously reported in other patients with IFNAR1 or IFNAR2 deficiency. This experiment of nature indicates that IFN-α/β are essential for anti–HSV-1 immunity in the CNS.

Authors

Paul Bastard, Jeremy Manry, Jie Chen, Jérémie Rosain, Yoann Seeleuthner, Omar AbuZaitun, Lazaro Lorenzo, Taushif Khan, Mary Hasek, Nicholas Hernandez, Benedetta Bigio, Peng Zhang, Romain Lévy, Shai Shrot, Eduardo J. Garcia Reino, Yoon-Seung Lee, Soraya Boucherit, Mélodie Aubart, Rik Gijsbers, Vivien Béziat, Zhi Li, Sandra Pellegrini, Flore Rozenberg, Nico Marr, Isabelle Meyts, Bertrand Boisson, Aurélie Cobat, Jacinta Bustamante, Qian Zhang, Emmanuelle Jouangy, Laurent Abel, Raz Somech, Jean-Laurent Casanova, Shen-Ying Zhang

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Figure 6

Abolition of the induction of ISGs in response to IFN-α/β in patient fibroblasts and EBV-B cells.

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Abolition of the induction of ISGs in response to IFN-α/β in patient fib...
(A) Fold change in IFIT1 and MX1 mRNA levels after the stimulation, with IFN-α2b, IFN-β, or IFN-γ, of SV40-fibroblasts from 2 healthy controls (C1, C2), P2, and IFNAR1–/–, IFNGR1–/–, and STAT1–/– patients for 2 hours or 8 hours. The GUS housekeeping gene was used as an expression control. Mean and SD values from 3 independent experiments are shown. (B) Fold change in IFIT1 and MX1 mRNA levels after the stimulation, with IFN-α2b, IFN-β, or IFN-γ, of EBV-B cells from 3 healthy controls (C1, C2, C3), P2, and the IFNAR1–/– and STAT1–/– patients for 2 hours or 8 hours. The housekeeping gene GUS was used as an expression control. Mean and SD values from 3 independent experiments are shown. (C) Heatmaps of genes differentially expressed after 2 or 8 hours of stimulation with IFN‑α2b or IFN‑γ, in primary fibroblasts from 3 healthy controls (C1, C2, C3), P2, the IFNAR1–/– p.V225fs patient, and an IFNGR1–/– patient. For each set of conditions, we show the genes significantly differentially expressed with respect to the control group, i.e., with a |log2(fold change [FC])| >1 and P < 0.05 after Benjamini-Hochberg correction, and genes with a |Δlog2(FC)| >1 between the control group and the IFNAR1–/– patient or the IFNGR1–/– patient after stimulation with IFN-α2b and IFN-γ, respectively. The gradient from blue to red represents increasing log2(FC). Genes are clustered by Euclidean distance. (D) Scatterplots of log2(FC) in RNA-Seq–quantified gene expression following stimulation with IFN‑α2b or IFN‑γ for 2 or 8 hours, in primary fibroblasts from P2 versus 3 healthy controls (C1, C2, and C3). Each dot represents a single gene.