TY - JOUR
T1 - Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency
AU - Bastard, Paul
AU - Manry, Jeremy
AU - Chen, Jie
AU - Rosain, Jérémie
AU - Seeleuthner, Yoann
AU - AbuZaitun, Omar
AU - Lorenzo, Lazaro
AU - Khan, Taushif
AU - Hasek, Mary
AU - Hernandez, Nicholas
AU - Bigio, Benedetta
AU - Zhang, Peng
AU - Lévy, Romain
AU - Shrot, Shai
AU - Reino, Eduardo J.Garcia
AU - Lee, Yoon Seung
AU - Boucherit, Soraya
AU - Aubart, Mélodie
AU - Gijsbers, Rik
AU - Béziat, Vivien
AU - Li, Zhi
AU - Pellegrini, Sandra
AU - Rozenberg, Flore
AU - Marr, Nico
AU - Meyts, Isabelle
AU - Boisson, Bertrand
AU - Cobat, Aurélie
AU - Bustamante, Jacinta
AU - Zhang, Qian
AU - Jouangy, Emmanuelle
AU - Abel, Laurent
AU - Somech, Raz
AU - Casanova, Jean Laurent
AU - Zhang, Shen Ying
N1 - Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021/1/4
Y1 - 2021/1/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85098877331&partnerID=8YFLogxK
U2 - 10.1172/JCI139980
DO - 10.1172/JCI139980
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C2 - 32960813
AN - SCOPUS:85098877331
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
M1 - e139980
ER -
