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

• Published in: The Journal of experimental medicine Vol. 221; no. 9
• Main Authors: Chan, Yi-Hao, Lundberg, Vanja, Le Pen, Jérémie, Yuan, Jiayi, Lee, Danyel, Pinci, Francesca, Volpi, Stefano, Nakajima, Koji, Bondet, Vincent, Åkesson, Sanna, Khobrekar, Noopur V, Bodansky, Aaron, Du, Likun, Melander, Tina, Mariaggi, Alice-Andrée, Seeleuthner, Yoann, Saleh, Tariq Shikh, Chakravarty, Debanjana, Marits, Per, Dobbs, Kerry, Vonlanthen, Sofie, Hennings, Viktoria, Thörn, Karolina, Rinchai, Darawan, Bizien, Lucy, Chaldebas, Matthieu, Sobh, Ali, Özçelik, Tayfun, Keles, Sevgi, AlKhater, Suzan A, Prando, Carolina, Meyts, Isabelle, Wilson, Michael R, Rosain, Jérémie, Jouanguy, Emmanuelle, Aubart, Mélodie, Abel, Laurent, Mogensen, Trine H, Pan-Hammarström, Qiang, Gao, Daxing, Duffy, Darragh, Cobat, Aurélie, Berg, Stefan, Notarangelo, Luigi D, Harschnitz, Oliver, Rice, Charles M, Studer, Lorenz, Casanova, Jean-Laurent, Ekwall, Olov, Zhang, Shen-Ying
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 2024
• Subjects: Adolescent; Brain Stem; Brain Stem - metabolism; Brain Stem - pathology; Brain Stem - virology; Brief Definitive Report; COVID-19; COVID-19 - genetics; COVID-19 - virology; Encephalitis; Encephalitis, Viral; Encephalitis, Viral - genetics; Encephalitis, Viral - pathology; Encephalitis, Viral - virology; Fibroblasts; Fibroblasts - metabolism; genetics; Human health and pathology; Humans; Immunodeficiency; Immunologi inom det medicinska området; Immunology in the medical area; Infectious diseases; Life Sciences; Male; Medicin och hälsovetenskap; metabolism; Microbiology and Parasitology; Neurons; Neurons - metabolism; Neurons - pathology; pathology; Pediatrics; Pediatrik; Rhombencephalon; Rhombencephalon - metabolism; SARS-CoV-2; SARS-CoV-2 - genetics; Viral; Virology
• ISSN: 0022-1007; 1540-9538; 1540-9538
• 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.