SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.
J Exp Med
; 221(9)2024 09 02.
Article
in En
| MEDLINE
| ID: mdl-39023559
ABSTRACT
Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron-intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Stem
/
SARS-CoV-2
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COVID-19
/
Neurons
Limits:
Adolescent
/
Humans
/
Male
Language:
En
Journal:
J Exp Med
Year:
2024
Document type:
Article
Affiliation country:
United States