GSE157948
Herpes simplex encephalitis in a patient   with a new form of  inherited IFNAR1 deficiency
Inborn errors of TLR3-dependent IFN-a/ß- and -?-mediated immunity in the central nervous system (CNS) can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-a/ß- and -? 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 from HSE at the age of two 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 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-a2b or IFN-ß, in terms of STAT1, STAT2 and STAT3 phosphorylation, or the induction of IFN-stimulated genes (ISGs). Transcriptome analysis revealed a complete abolition of genome-wide ISG induction in response to IFN-a2b in IFNAR1-deficient fibroblasts from the patient. These fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-a2b or IFN-ß. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This experiment of Nature indicates that IFN-a/ß are essential for anti-HSV-1 immunity in the CNS. Overall design: Total RNA profiles from primary fibroblasts of the HSE IFNAR1 patient, a previously validated IFNGR1 patient, a previously validated IFNAR1 patient, and three healthy controls. Each library was sequenced twice.