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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 Article has an altmetric score of 54

Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

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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 1

Homozygous deletion in IFNAR1 in a patient who died from HSE and her cousin.

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Homozygous deletion in IFNAR1 in a patient who died from HSE and her cou...
(A) Family pedigree showing the segregation of the IFNAR1 mutant (MT) allele. Double lines connect the 2 parents with consanguinity. The filled black symbol indicates the proband (patient 1, P1) with HSE, the filled gray symbols indicate individuals with viral diseases other than HSE, and the open symbols indicate healthy family members. E?, unknown IFNAR1 genotype. (B) Brain imaging showing HSE lesions in P1. Left: Post-contrast T2-FLAIR image showing diffuse cortical and subcortical edema on temporo-occipital regions accompanied by leptomeningeal enhancement (yellow triangles), compatible with meningoencephalitis. There are also parenchymal lesions, involving the left thalamus and base of the frontal lobes, indicated by yellow arrowhead. Right: Noncontrast head CT, performed 7 days later, showing diffuse brain edema with multiple parenchymal hemorrhages in the edematous areas previously identified (yellow triangles). (C) IFNAR1 from leukocyte gDNA from the patients and other relatives, amplified by PCR with a forward primer binding to exon 10 and a reverse primer binding to the 3′-UTR part of exon 11. The result shown is representative of 2 independent experiments. (D) Top: Sanger sequencing results for IFNAR1 from patient leukocyte gDNA. Bottom: Schematic diagram of the IFNAR1 gene in the gDNA, with 11 coding exons, and a red box representing the location of the deletion found in the patients. The result shown is representative of 3 independent experiments on 2 independently drawn samples.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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