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

Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem infections with herpes simplex virus, influenza virus, or norovirus. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited deficiency of DBR1 in a 14-year-old boy with no history of prior severe infectious disease 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. Moreover, DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection, unlike hindbrain neurons deficient for the type I IFN receptor. Exogenous type I IFN only partially rescues this phenotype. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hPSC-derived hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, the expression of exogenous RNA lariats mimicking DBR1 deficiency increased the susceptibility of WT hPSC-derived hindbrain neurons to SARS-CoV-2 infection. Inborn errors of human DBR1 impair type I IFN-independent hindbrain neuron-intrinsic antiviral immunity, thereby conferring a predisposition to viral infections of the brainstem, including SARS-CoV-2 brainstem encephalitis.