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

Chan Y.-H.; Lundberg V.; Le Pen J.; Yuan J.; Lee D.; Pinci F.; Volpi S.; Nakajima K.; Bondet V.; Åkesson S.; Khobrekar N.V.; Bodansky A.; Du L.; Melander T.; Mariaggi A.-A.; Seeleuthner Y.; Saleh T.S.; Chakravarty D.; Marits P.; Dobbs K.; Vonlanthen S.; Hennings V.; Thörn K.; Rinchai D.; Bizien L.; Chaldebas M.; Sobh A.; Özçelik T.; Keles S.; Alkhater S.A.; Prando C.; Meyts I.; Wilson M.R.; Rosain J.; Jouanguy E.; Aubart M.; Abel L.; Mogensen T.H.; Pan-Hammarström Q.; Gao D.; Duffy D.; Cobat A.; Berg S.; Notarangelo L.D.; Harschnitz O.; Rice C.M.; Studer L.; Casanova J.-L.; Ekwall O.; Zhang S.-Y.; Bastard P.; Borghesi A.; Bousfiha A.; Boyarchuk O.; Brodin P.; Bustamante J.; Casari G.; Chevalier R.; Christodoulou J.; Colobran R.; Condino-Neto A.; Aldave Becerra J.C.; Arkin L.; Andreakos E.; Thorball C.W.; Espinosa S.; Flores C.; Geraldo A.; Halwani R.; Hatipoğlu N.; Melaiki B.; Fellay J.; Gagro A.; Itan Y.; Jeewandara C.; Haerynck F.; Mansouri D.; Naesens L.; Ng L.F.P.; Okamoto K.; Soler- Palacin P.; Renia L.; Onofre A.P.; Resnick I.B.; Ranco Restrepo J.L.F.; Rivière J.G.; Scherbina A.; Šedivá A.; Seppänen M.R.J.; Su H.; Tangye S.G.; Temel S.G.; Tayoun A.A.; Turvey S.; Furkan Uddin K.M.; van de Beek D.; Le Voyer T.; Vinh D.C. · Journal of Experimental Medicine (2024) · DOI: 10.1084/jem.20231725

Resumen

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 boywho 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 ofWT 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.