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 3

The MT IFNAR1 protein is expressed on the cell surface, truncated, and does not bind TYK2.

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The MT IFNAR1 protein is expressed on the cell surface, truncated, and d...
(A) Real-time qPCR for IFNAR1 in HEK293T cells transiently transfected with IFNAR1 cDNA constructs; GUS was used as an expression control. Mean value and SD from 3 independent experiments with technical duplicates in each experiment. (B) Western blot (WB) of IFNAR1 in HEK293T cells transiently transfected with IFNAR1 cDNA constructs, and the same samples treated with PNGase F to inhibit glycosylation. An antibody recognizing the N-terminal (N-ter) part of the IFNAR1 protein was used. GAPDH was used as a loading control. A representative blot from 3 independent experiments is shown. NT, nontransfected; EV, empty vector; V225fs, variant of the previously reported IFNAR1–/– patient. TTT, treatment. (C) WB of IFNAR1 in HEK293T cells transiently transfected with IFNAR1 constructs. An antibody recognizing the C-terminal (C-ter) part of the protein was used. GAPDH was used as a loading control. A representative blot from 2 independent experiments is shown. (D) Extracellular FACS staining and mean fluorescence intensity (MFI) of IFNAR1 in HEK cells transiently transfected with IFNAR1 cDNA constructs, with an antibody recognizing the N-terminus of the protein. Cells were not permeabilized. Results representative of 3 independent experiments are shown. (E) MFI of IFNAR1 surface expression, represented graphically. Mean values and SD from 3 independent experiments are shown. (F) Immunofluorescence staining, as assessed by confocal microscopy in HeLa cells transiently transfected with IFNAR1 cDNA constructs. An antibody against the N-terminus of IFNAR1 was used (green), and membranes were stained for wheat germ agglutinin (WGA) (purple). The nuclei were stained with DAPI (blue). The images shown are representative of 3 independent experiments. (G) WB for TYK2 and IFNAR1 after coimmunoprecipitation from protein extracts of HEK293T cells cotransfected with WT or MT IFNAR1 cDNA constructs and WT TYK2. The images presented are representative of 3 independent experiments.