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

• DOI: 10.1084/jem.20231725
• Publication Date: 2024-07-18T13:57:47Z
• Authors: Yi-Hao Chan; Vanja Lundberg; Jérémie Le Pen; Jiayi Yuan; Danyel Lee; Francesca Pinci; Stefano Volpi; Koji Nakajima; Vincent Bondet; Sanna Åkesson; Noopur V. Khobrekar; Aaron Bodansky; Likun Du; Tina Melander; Alice-Andrée Mari...; Yoann Seeleuthner; Tariq Shikh Saleh; Debanjana Chakrav...; Per Marits; Kerry Dobbs; Sofie Vonlanthen; Viktoria Hennings; Karolina Thörn; Darawan Rinchai; Lucy Bizien; Matthieu Chaldebas; Ali Sobh; Tayfun Özçelik; Sevgi Keles; Suzan A. AlKhater; Carolina Prando; Isabelle Meyts; ; Paul Bastard; Alessandro Borghesi; Aziz Bousfiha; Oksana Boyarchuk; Petter Brodin; Jacinta Bustamante; Giorgio Casari; Rémi Chevalier; John Christodoulou; Roger Colobran; Antonio Condino-Neto; Juan Carlos Aldav...; Lisa Arkin; Evangelos Andreakos; Christian W. Thor...; Sara Espinosa; Carlos Flores; Amyrath Geraldo; Rabih Halwani; Nevin Hatipoğlu; Brahim Melaiki; Jacques Fellay; Alenka Gagro; Yuval Itan; Chandima Jeewandara; Filomeen Haerynck; Davood Mansouri; Leslie Naesens; Lisa F.P. Ng; Keisuke Okamoto; Pere Soler-Palacin; Laurent Renia; Aurora Pujol Onofre; Igor B. Resnick; José Luis Franco ...; Jacques G. Rivière; Anna Scherbina; Anna Šedivá; Mikko R.J. Seppänen; Helen Su; Stuart G Tangye; Sehime G. Temel; Ahmad Abou Tayoun; Stuart Turvey; K.M. Furkan Uddin; Diederik van de Beek; Tom Le Voyer; Donald C. Vinh; Shen-Ying Zhang; Jean-Laurent Casa...; Michael R. Wilson; Jérémie Rosain; Emmanuelle Jouanguy; Mélodie Aubart; Laurent Abel; Trine H. Mogensen; Qiang Pan-Hammars...; Daxing Gao; Darragh Duffy; Aurélie Cobat; Stefan Berg; Luigi D. Notarangelo; Oliver Harschnitz; Charles M. Rice; Lorenz Studer; Jean-Laurent Casa...; Olov Ekwall; Shen-Ying Zhang
• Keywords: Male; 570; Adolescent; Immunology; VARIANT; 610; Research & Experimental Medicine; IMMUNITY; INFECTION; Medicine and Health Sciences; Immunodeficiency; Humans; Viral; Encephalitis, Viral; Neurons; Science & Technology; SARS-CoV-2; Brief Definitive Report; Biology and Life Sciences; COVID-19; Fibroblasts; Rhombencephalon; Medicine, Research & Experimental; CELLS; Encephalitis; Life Sciences & Biomedicine; Brain Stem

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.