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

Abstract

Inborn errors of TLR3-dependent IFN-a/b-and-l-mediated immunity in the central nervous system (CNS) can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-a/b and-l 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, 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-a2b or IFN-b, 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-a2b or IFN-b. 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-a/b are essential for anti-HSV-1 immunity in the CNS.

Life-Threatening Influenza, Hemophagocytic Lymphohistiocytosis and Probable Vaccine-Strain Varicella in a Novel Case of Homozygous STAT2 Deficiency

“…A phenotype of vulnerability to severe IAV has not been reported to date in selective defects of either IFN-I signaling [i.e. IFNAR1 ( 33 , 34 ) or IFNAR2 ( 35 ) deficiency], nor IFN-III signaling [i.e. IL10RB deficiency ( 36 )], suggesting that neither pathway in isolation is essential.…”

TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons

“…The genetic dissection of various viral diseases, including coronavirus disease 2019 (COVID-19) (73-75), may help to delineate the roles of human TLR3 and other IFN-inducing sensors in host defense. It also seems likely that deficiencies of other type I IFN responsiveness circuit genes (e.g., IRF7, IRF9, STAT1, STAT2, IFNAR1, IFNAR2) render patients prone to a broad spectrum of viral diseases, other than the previously reported phenotypes including severe influenza pneumonia (IRF7, IRF9), HSE (IFNAR1, STAT1), and severe adverse reactions to live attenuated viral vaccines (IRF9, STAT1, STAT2, IFNAR1, IFNAR2) (12,17,40,(76)(77)(78)(79), partly due to the low basal levels of IFN-β, IFN-λ, and ISG in tissue-specific cells. Our findings highlight the importance of host cell-intrinsic and constitutive, as opposed to pathogen-induced, IFN and ISG immunity in antiviral defenses, particularly during early stages of viral J Clin Invest.…”

“…The pathogenesis of HSE remained unexplained until our description of the first genetic etiologies for this disease (9,10). Germline HSE-causing mutations have since been reported in 7 genes of the TLR3 pathway (TLR3, UNC93B1, TRIF, TRAF3, TBK1, IRF3, NEMO) and 2 genes of the IFN-α/β receptor pathway (IFNAR1, STAT1) (9)(10)(11)(12)(13)(14)(15)(16)(17). UNC-93B is a membrane-bound molecule that regulates the signaling of endosomal TLR3, TLR7, TLR8, and TLR9 by binding to their transmembrane domains and Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity.…”

Insufficient type I IFN immunity underlies life-threatening COVID-19 pneumonia

“…Nous avons précédemment identifié des variants dans les gènes IRF7, IRF9 et TLR3 comme étant des causes monogéniques de pneumopathies grippales potentiellement mortelles, les défauts de ces trois gènes entraînant une altération de la production et de l'amplification de l'IFN de type I en réponse aux infections virales [12][13][14]. Nous avons également identifié, avec d'autres équipes, des mutations dans d'autres gènes faisant partie du circuit de la production ou de la réponse aux IFN de type I, comme étant responsables de l'encéphalite herpétique ou d'infections graves dues à des vaccins vivants atténués [19][20][21][22][23][24][25][26]. Nous nous sommes donc concentrés sur 13 loci du circuit de l'IFN de type I comme gènes candidats pour les pneumonies COVID-19 sévères : TLR3, UNC93B1, TRAF3, TICAM1/TRIF, TBK1, IKBKG/NEMO, IRF3, IRF7, IFNAR1, IFNAR2, STAT1, STAT2 et IRF9.…”

“…We have identified IRF7, IRF9, and TLR3 variants as monogenic causes of lifethreatening influenza pneumonia, with defects of all three of these genes resulting in impaired type I IFN production and amplification in response to viral infections [12][13][14]. We and others have also identified other monogenic defects of the related type I IFN circuit responsible for herpes simplex encephalitis (HSE) or severe infections due to live attenuated vaccines [19][20][21][22][23][24][25][26]. We therefore focused on 13 loci from the type I IFN circuit as candidates causal genes for severe COVID-19: TLR3, UNC93B1, TRAF3, TICAM1/TRIF, TBK1, IKBKG/NEMO, IRF3, IRF7, IF-NAR1, IFNAR2, STAT1, STAT2, and IRF9.…”