SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.

Area of Science:

• Genetics
• Neuroscience
• Virology

Background:

• Inherited deficiency of RNA lariat-debranching enzyme 1 (DBR1) is a rare cause of brainstem encephalitis.
• The cellular mechanisms and viral predispositions associated with DBR1 deficiency are not well understood.

Purpose of the Study:

• To investigate the role of inherited DBR1 deficiency in SARS-CoV-2 brainstem encephalitis.
• To elucidate the cellular basis of DBR1 deficiency-related viral susceptibility in the brainstem.

Main Methods:

• Clinical case report of a 14-year-old boy with DBR1 deficiency and SARS-CoV-2 encephalitis.
• Analysis of DBR1 protein levels and RNA lariat accumulation in patient-derived fibroblasts and hindbrain neurons.
• Functional studies involving expression of wild-type DBR1 and exogenous RNA lariats in cell models.
• Assessment of SARS-CoV-2 susceptibility in DBR1-deficient and wild-type neurons.

Main Results:

• The patient was homozygous for a pathogenic DBR1 variant (I120T), leading to low DBR1 protein and high RNA lariats.
• DBR1-deficient hindbrain neurons showed increased susceptibility to SARS-CoV-2 infection.
• Restoring DBR1 function corrected RNA lariat accumulation.
• Exogenous RNA lariats mimicked DBR1 deficiency, increasing viral susceptibility in wild-type neurons.

Conclusions:

• Inborn errors of DBR1 compromise intrinsic antiviral immunity in hindbrain neurons.
• DBR1 deficiency predisposes to viral brainstem infections, notably SARS-CoV-2 encephalitis.
• This study identifies DBR1 deficiency as a genetic risk factor for severe brainstem viral infections.