TY - JOUR
T1 - SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency
AU - COVID Human Genetic Effort
AU - Chan, Yi-Hao
AU - Lundberg, Vanja
AU - Le Pen, Jérémie
AU - Yuan, Jiayi
AU - Lee, Danyel
AU - Pinci, Francesca
AU - Volpi, Stefano
AU - Nakajima, Koji
AU - Bondet, Vincent
AU - Åkesson, Sanna
AU - Khobrekar, Noopur V
AU - Bodansky, Aaron
AU - Du, Likun
AU - Melander, Tina
AU - Mariaggi, Alice-Andrée
AU - Seeleuthner, Yoann
AU - Saleh, Tariq Shikh
AU - Chakravarty, Debanjana
AU - Marits, Per
AU - Dobbs, Kerry
AU - Vonlanthen, Sofie
AU - Hennings, Viktoria
AU - Thörn, Karolina
AU - Rinchai, Darawan
AU - Bizien, Lucy
AU - Chaldebas, Matthieu
AU - Sobh, Ali
AU - Özçelik, Tayfun
AU - Keles, Sevgi
AU - AlKhater, Suzan A
AU - Prando, Carolina
AU - Meyts, Isabelle
AU - Wilson, Michael R
AU - Rosain, Jérémie
AU - Jouanguy, Emmanuelle
AU - Aubart, Mélodie
AU - Abel, Laurent
AU - Mogensen, Trine H
AU - Pan-Hammarström, Qiang
AU - Gao, Daxing
AU - Duffy, Darragh
AU - Cobat, Aurélie
AU - Berg, Stefan
AU - Notarangelo, Luigi D
AU - Harschnitz, Oliver
AU - Rice, Charles M
AU - Studer, Lorenz
AU - Casanova, Jean-Laurent
AU - Ekwall, Olov
AU - Zhang, Shen-Ying
AU - van de Beek, D.
N1 - Publisher Copyright:
© 2024 Chan et al.
PY - 2024/9/2
Y1 - 2024/9/2
N2 - 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.
AB - 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.
KW - Immunodeficiency
UR - https://www.scopus.com/pages/publications/85205932169
U2 - 10.1084/jem.20231725
DO - 10.1084/jem.20231725
M3 - Article
C2 - 39023559
SN - 0022-1007
VL - 221
JO - Journal of experimental medicine
JF - Journal of experimental medicine
IS - 9
M1 - e20231725
ER -
SDG 3 Good Health and Well-being