tetano
Editor, Senior Moderator
J Exp Med
. 2024 Sep 2;221(9):e20231725.
doi: 10.1084/jem.20231725. Epub 2024 Jul 18. SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency
Yi-Hao Chan[SUP] #[/SUP][SUP] 1 [/SUP], Vanja Lundberg[SUP] #[/SUP][SUP] 2 3 [/SUP], Jérémie Le Pen[SUP] #[/SUP][SUP] 4 [/SUP], Jiayi Yuan[SUP] #[/SUP][SUP] 5 [/SUP], Danyel Lee[SUP] #[/SUP][SUP] 1 6 7 [/SUP], Francesca Pinci[SUP] #[/SUP][SUP] 8 [/SUP], Stefano Volpi[SUP] #[/SUP][SUP] 9 10 [/SUP], Koji Nakajima[SUP] 1 [/SUP], Vincent Bondet[SUP] 11 [/SUP], Sanna Åkesson[SUP] 3 [/SUP], Noopur V Khobrekar[SUP] 5 [/SUP], Aaron Bodansky[SUP] 12 [/SUP], Likun Du[SUP] 13 [/SUP], Tina Melander[SUP] 14 [/SUP], Alice-Andrée Mariaggi[SUP] 15 [/SUP], Yoann Seeleuthner[SUP] 6 7 [/SUP], Tariq Shikh Saleh[SUP] 16 [/SUP], Debanjana Chakravarty[SUP] 17 18 [/SUP], Per Marits[SUP] 19 20 [/SUP], Kerry Dobbs[SUP] 21 [/SUP], Sofie Vonlanthen[SUP] 19 20 [/SUP], Viktoria Hennings[SUP] 2 3 [/SUP], Karolina Thörn[SUP] 3 [/SUP], Darawan Rinchai[SUP] 1 [/SUP], Lucy Bizien[SUP] 6 7 [/SUP], Matthieu Chaldebas[SUP] 1 [/SUP], Ali Sobh[SUP] 22 [/SUP], Tayfun Özçelik[SUP] 23 [/SUP], Sevgi Keles[SUP] 24 [/SUP], Suzan A AlKhater[SUP] 25 26 [/SUP], Carolina Prando[SUP] 27 [/SUP], Isabelle Meyts[SUP] 28 [/SUP]; COVID Human Genetic Effort; Michael R Wilson[SUP] 17 18 [/SUP], Jérémie Rosain[SUP] 1 6 7 [/SUP], Emmanuelle Jouanguy[SUP] 1 6 7 [/SUP], Mélodie Aubart[SUP] 6 7 29 [/SUP], Laurent Abel[SUP] 1 6 7 [/SUP], Trine H Mogensen[SUP] 30 [/SUP], Qiang Pan-Hammarström[SUP] 13 [/SUP], Daxing Gao[SUP] 31 32 [/SUP], Darragh Duffy[SUP] 11 [/SUP], Aurélie Cobat[SUP] 6 7 [/SUP], Stefan Berg[SUP] 2 [/SUP], Luigi D Notarangelo[SUP] 21 [/SUP], Oliver Harschnitz[SUP] #[/SUP][SUP] 8 [/SUP], Charles M Rice[SUP] #[/SUP][SUP] 4 [/SUP], Lorenz Studer[SUP] #[/SUP][SUP] 5 [/SUP], Jean-Laurent Casanova[SUP] #[/SUP][SUP] 1 6 7 33 34 [/SUP], Olov Ekwall[SUP] #[/SUP][SUP] 2 3 [/SUP], Shen-Ying Zhang[SUP] #[/SUP][SUP] 1 6 7 [/SUP]
Collaborators, Affiliations
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.
. 2024 Sep 2;221(9):e20231725.
doi: 10.1084/jem.20231725. Epub 2024 Jul 18. SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency
Yi-Hao Chan[SUP] #[/SUP][SUP] 1 [/SUP], Vanja Lundberg[SUP] #[/SUP][SUP] 2 3 [/SUP], Jérémie Le Pen[SUP] #[/SUP][SUP] 4 [/SUP], Jiayi Yuan[SUP] #[/SUP][SUP] 5 [/SUP], Danyel Lee[SUP] #[/SUP][SUP] 1 6 7 [/SUP], Francesca Pinci[SUP] #[/SUP][SUP] 8 [/SUP], Stefano Volpi[SUP] #[/SUP][SUP] 9 10 [/SUP], Koji Nakajima[SUP] 1 [/SUP], Vincent Bondet[SUP] 11 [/SUP], Sanna Åkesson[SUP] 3 [/SUP], Noopur V Khobrekar[SUP] 5 [/SUP], Aaron Bodansky[SUP] 12 [/SUP], Likun Du[SUP] 13 [/SUP], Tina Melander[SUP] 14 [/SUP], Alice-Andrée Mariaggi[SUP] 15 [/SUP], Yoann Seeleuthner[SUP] 6 7 [/SUP], Tariq Shikh Saleh[SUP] 16 [/SUP], Debanjana Chakravarty[SUP] 17 18 [/SUP], Per Marits[SUP] 19 20 [/SUP], Kerry Dobbs[SUP] 21 [/SUP], Sofie Vonlanthen[SUP] 19 20 [/SUP], Viktoria Hennings[SUP] 2 3 [/SUP], Karolina Thörn[SUP] 3 [/SUP], Darawan Rinchai[SUP] 1 [/SUP], Lucy Bizien[SUP] 6 7 [/SUP], Matthieu Chaldebas[SUP] 1 [/SUP], Ali Sobh[SUP] 22 [/SUP], Tayfun Özçelik[SUP] 23 [/SUP], Sevgi Keles[SUP] 24 [/SUP], Suzan A AlKhater[SUP] 25 26 [/SUP], Carolina Prando[SUP] 27 [/SUP], Isabelle Meyts[SUP] 28 [/SUP]; COVID Human Genetic Effort; Michael R Wilson[SUP] 17 18 [/SUP], Jérémie Rosain[SUP] 1 6 7 [/SUP], Emmanuelle Jouanguy[SUP] 1 6 7 [/SUP], Mélodie Aubart[SUP] 6 7 29 [/SUP], Laurent Abel[SUP] 1 6 7 [/SUP], Trine H Mogensen[SUP] 30 [/SUP], Qiang Pan-Hammarström[SUP] 13 [/SUP], Daxing Gao[SUP] 31 32 [/SUP], Darragh Duffy[SUP] 11 [/SUP], Aurélie Cobat[SUP] 6 7 [/SUP], Stefan Berg[SUP] 2 [/SUP], Luigi D Notarangelo[SUP] 21 [/SUP], Oliver Harschnitz[SUP] #[/SUP][SUP] 8 [/SUP], Charles M Rice[SUP] #[/SUP][SUP] 4 [/SUP], Lorenz Studer[SUP] #[/SUP][SUP] 5 [/SUP], Jean-Laurent Casanova[SUP] #[/SUP][SUP] 1 6 7 33 34 [/SUP], Olov Ekwall[SUP] #[/SUP][SUP] 2 3 [/SUP], Shen-Ying Zhang[SUP] #[/SUP][SUP] 1 6 7 [/SUP]
Collaborators, Affiliations
- PMID: 39023559
- DOI: 10.1084/jem.20231725
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.