SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency Journal Article
| Authors: | 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. K.; 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.; Ozçelik, T.; Keles, S.; AlKhater, S. A.; Prando, C.; Meyts, I.; COVID Human Genetic Effort; 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. |
| Article Title: | SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency |
| Abstract: | Chan et al. report inherited DBR1 deficiency as a genetic etiology of isolated SARS-CoV-2 brainstem encephalitis. DBR1 I120T/I120T patient-specific hPSC-derived hindbrain neurons display enhanced accumulation of RNA lariats resulting in increased susceptibility to SARS-CoV-2 infection, thereby underlying SARS-CoV-2 brainstem encephalitis. 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. |
| Keywords: | infection; immunity; cells; variant |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 221 |
| Issue: | 9 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2024-07-01 |
| Start Page: | e20231725 |
| Language: | English |
| ACCESSION: | WOS:001271884300001 |
| DOI: | 10.1084/jem.20231725 |
| PROVIDER: | wos |
| PMCID: | PMC11256911 |
| PUBMED: | 39023559 |
| Notes: | Source: Wos |
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