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 5

Patient EBV-B cells express a truncated IFNAR1 and do not respond to IFN-α/β.

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Patient EBV-B cells express a truncated IFNAR1 and do not respond to IFN...
(A) IFNAR1 mRNA levels, in PBMCs from 1 healthy control, P1’s father (III.2), and P2. The GUS housekeeping gene was used as an expression control. Mean (and SD) values from 3 independent experiments, each with technical duplicates, are shown. (B) IFNAR1 mRNA levels in EBV-B cells from 2 healthy controls, P2, and previously reported IFNAR1–/–, IFNGR1–/–, and STAT1–/– patients; the housekeeping gene GUS was used as an expression control. Mean (and SD) values from 3 independent experiments, each with technical duplicates, are shown. (C) Extracellular FACS staining of IFNAR1 in EBV-B cells from 4 healthy controls, P2, and IFNAR1–/–, IFNGR1–/–, and STAT1–/– patients. Cells were not permeabilized. An antibody recognizing the N-terminal part of the protein was used. The results shown are representative of 3 independent experiments. (D) WB of IFNAR1 in EBV-B cells from 2 healthy controls (C1, C2), P2, and IFNAR1–/–, IFNGR1–/–, and STAT1–/– patients. An antibody recognizing the N-terminal side of the protein was used. GAPDH was used as a loading control. A representative blot from 3 independent experiments is shown. (E) MFI after intracellular FACS staining of p-STAT1, p-STAT2, and p-STAT3, in EBV-B cells stimulated with 1000 U/mL IFN-α2b, IFN-β, IFN-λ, or IFN-γ for 15 minutes. The cells used were from 3 healthy controls (C1, C2, C3), P2, and IFNAR1–/–, IFNGR1–/–, and STAT1–/– patients. MFI (and SD) values from 3 independent experiments are shown.