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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Research Article Immunology Infectious disease

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 2

The IFNAR1 deletion leads to aberrant cDNA splicing.

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The IFNAR1 deletion leads to aberrant cDNA splicing. (A) cDNA TOPO cloni...
(A) cDNA TOPO cloning and sequencing results demonstrating complete aberrant splicing of IFNAR1 in PBMCs from P2. At least 100 transcripts were sequenced for the patient and the control. The result shown is the sum of 2 independent experiments. (B) Schematic diagram of the full-length cDNA of WT and MT IFNAR1. Sequencing results demonstrated aberrant splicing and an absence of the coding sequence of IFNAR1 exon 11 in PBMCs from P2. The blue box indicates the 97-bp intronic insertion. The red box indicates the 473-bp deletion. The exons are numbered in roman numerals (I–XI). The 5′- or 3′-UTR is shown in light gray, and the coding sequences of the exons are shown in dark gray. (C) RNA-Seq results for primary fibroblasts (top) or PBMCs (bottom) showing the coverage of IFNAR1 from intron 10 to exon 11, in healthy controls and P2, demonstrating an insertion and the deletion of the coding sequence of exon 11 and part of the 3′-UTR. For primary fibroblasts, the results shown are representative of 5 technical replicates (corresponding to different RNA-Seq conditions). (D) Schematic diagram of the WT and MT IFNAR1 proteins, with the 4 fibronectin type III subdomains (SD1–SD4) and the TYK2 interaction domain (in black). The signal peptide is denoted “SP” and the transmembrane domain “TM.” The mutation reported in this study is indicated in red, and previously reported mutations are indicated in violet.