Department of Molecular Biology and Genetics

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Browsing Department of Molecular Biology and Genetics by Author "Abel, Laurent"

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    A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity
    (Rockefeller University Press, 2024-12-16) Qureshah, Fahd Al; Pen, Jérémie Le; Weerd, Nicole A. de; Moncada-Velez, Marcela; Materna, Marie; Lin, Daniel C.; Milisavljevic, Baptiste; Vianna, Fernanda; Bizien, Lucy; Lorenzo, Lazaro; Lecuit, Marc; Pommier, Jean-David; Keles, Sevgi; Özçelik, Tayfun; Pedraza-Sanchez, Sigifredo; Prost, Nicolas de; Zein, Loubna El; Hammoud, Hassan; Ng, Lisa F.P.; Halwani, Rabih; Sharif-Askari, Narjes Saheb; Lau, Yu Lung; Tam, Anthony R.; Singh, Neha; Bhattad, Sagar; Berkun, Yackov; Chantratita, Wasun; Aguilar-López, Raúl; Shahrooei, Mohammad; Abel, Laurent; Bastard, Paul; Jouanguy, Emmanuelle; Béziat, Vivien; Zhang, Peng; Rice, Charles M.; Cobat, Aurélie; Zhang, Shen-Ying; Hertzog, Paul J.; Casanova, Jean-Laurent; Zhang, Qian
    Autosomal recessive deficiency of the IFNAR1 or IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR1 and IFNAR2 deficiency in Western Polynesia and the Arctic, respectively. We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β. Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%). Cells heterozygous for these variants display a dominant phenotype in vitro with impaired responses to IFN-α and -ω, but not -β, and viral susceptibility. Negative dominance, rather than haploinsufficiency, accounts for this dominance. Patients heterozygous for these variants are prone to viral diseases, attesting to both the dominance of these variants clinically and the importance of IFN-α and -ω for protective immunity against some viruses.
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    Author Correction: A global effort to dissect the human genetic basis of resistance to SARS-CoV-2 infection (Nature Immunology, (2022), 23, 2, (159-164), 10.1038/s41590-021-01030-z)
    (Springer Nature, 2022-02) Andreakos, Evangelos; Abel, Laurent; Vinh, Donald C.; Kaja, Elżbieta; Drolet, Beth A.; Zhang, Qian; O’Farrelly, Cliona; Novelli, Giuseppe; Rodríguez-Gallego, Carlos; Haerynck, Filomeen; Prando, Carolina; Pujol, Aurora; Bastard, Paul; Biggs, Catherine M.; Bigio, Benedetta; Boisson, Bertrand; Bolze, Alexandre; Bondarenko, Anastasiia; Brodin, Petter; Chakravorty, Samya; Christodoulou, John; Cobat, Aurelié; Condino-Neto, Antonio; Constantinescu, Stefan N.; Feldman, Hagit Baris; Fellay, Jacques; Halwani, Rabih; Jouanguy, Emmanuelle; Lau, Yu-Lung; Meyts, Isabelle; Mogensen, Trine H.; Okada, Satoshi; Okamoto, Keisuke; Özçelik, Tayfun; Pan-Hammarström, Qiang; Planas, Anna M.; Puel, Anne; Quintana-Murci, Lluis; Renia, Laurent; Resnick, Igor; Sediva, Anna; Shcherbina, Anna; Slaby, Ondrej; Tancevski, Ivan; Turvey, Stuart E.; Uddin, K. M. Furkan; van de Beek, Diederik; Zatz, Mayana; Zawadzki, Pawel; Zhang, Shen-Ying; Su, Helen C.; Casanova, Jean-Laurent; Spaan, András N.
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    Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C)
    (Rockefeller University Press, 2024-11-22) Bellos, Evangelos; Santillo, Dilys; Vantourout, Pierre; Jackson, Heather R.; Duret, Amedine; Hearn, Henry; Seeleuthner, Yoann; Talouarn, Estelle; Hodeib, Stephanie; Patel, Harsita; Powell, Oliver; Yeoh, Sophya; Mustafa, Sobia; Habgood-coote, Dominic; Nichols, Samuel; Elorrieta, Leire Estramiana; D’souza, Giselle; Wright, Victoria J.; Estrada-rivadeneyra, Diego; Tremoulet, Adriana H.; Dummer, Kirsten B.; Netea, Stejara A.; Condino-neto, Antonio; Lau, Yu Lung; Cuadros, Esmeralda Núñez; Toubiana, Julie; Pena, Marisol Holanda; Rieux-laucat, Frédéric; Luyt, Charles-edouard; Haerynck, Filomeen; Mège, Jean Louis; Chakravorty, Samya; Haddad, Elie; Morin, Marie-paule; Akcan, Özge Metin; Keles, Sevgi; Emiroglu, Melike; Alkan, Gulsum; Öz, Sadiye Kübra Tüter; Bozdemir, Sefika Elmas; Morelle, Guillaume; Volokha, Alla; Kendir-demirkol, Yasemin; Sözeri, Betul; Coskuner, Taner; Gulhan, Aysun Yahsi, Belgin; Kanik-yuksek, Saliha; Bayhan, Gulsum Iclal; Ozkaya-parlakay, Aslinur; Yesilbas, Osman; Hatipoglu, Nevin; Özçelik, Tayfun; Belot, Alexandre; Chopin, Emilie; Barlogis, Vincent; Sevketoglu, Esra; Menentoglu, Emin; Aydin, Zeynep Gokce Gayretli; Bloomfield, Marketa; Alkhater, Suzan A.; Cyrus, Cyril; Stepanovskiy, Yuriy; Bondarenko, Anastasiia; Öz, Fatma Nur; Polat, Meltem; Fremuth, Jiří; Lebl, Jan; Geraldo, Amyrath; Jouanguy, Emmanuelle; Carter, Michael J.; Wellman, Paul; Peters, Mark; Diego, Rebeca Pérez De; Edwards, Lindsey Ann; Chiu, Christopher; Noursadeghi, Mahdad; Bolze, Alexandre; Shimizu, Chisato; Kaforou, Myrsini; Hamilton, Melissa Shea; Herberg, Jethro A.; Schmitt, Erica G.; Rodriguez-palmero, Agusti; Pujol, Aurora; Kim, Jihoon; Cobat, Aurélie; Abel, Laurent; Zhang, Shen-ying; Casanova, Jean-laurent; Kuijpers, Taco W.; Burns, Jane C.; Levin, Michael; Hayday, Adrian C.; Sancho-shimizu, Vanessa
    Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, “burdenMC,” which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5-5.3, P < 10-6). BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2.
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    Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children
    (Rockefeller University Press, 2024-01-04) Bastard, Paul; Gervais, Adrian; Taniguchi, Maki; Saare, Liisa; Särekannu, Karita; Voyer, Tom le; Philippot, Quentin; Rosain, Jeremie; Bizien, Lucy; Asano, Takaki; Garcia-Prat, Marina; Parra-Martínez, Alba; Migaud, Mélanie; Tsumura, Miyuki; Conti, Francesca; Belot, Alexandre; Rivière, Jacques G.; Morio, Tomohiro; Tanaka, Junko; Javouhey, Etienne; Haerynck, Filomeen; Duvlis, Sotirija; Özçelik, Tayfun; Keles, Sevgi; Redondo, yacine tandjaoui-lambiotte; Escoda, Simon; Husain, Maya; Pan-Hammarström, Qiang; Hammarström, Lennart; Gloria, Ahlijah; Haidar, Anthony ABI; Soudee, Camille; Abolhassani, Hassan; Sahanic, Sabina; Tancevski, Ivan; Nukui, Yoko; Hayakawa, Seiichi; Chrousos, George P.; Michos, Athanasios; Tatsi, Elizabeth; Filippatos, Filippos; Rodriguez-Palmero, Agusti; García, Jesús Troya; Tipu, Imran; Meyts, Isabelle; Roussel, Lucie; Ostrowski, Sisse Rye; Schidlowski, Laire; Prando, Carolina; Condino-Neto, Antonio; Cheikh, Nathalie; Bousfiha, Ahmed Aziz; Bakkouri, Jalila EL; Peterson, Pärt; Pujol, Aurora; Lévy, Romain; Quartier, Pierre; Vinh, Donald C.; Boisson, Bertrand; Béziat, Vivien; Zhang, Shen-Ying; Borghesi, Alessandro; Pession, Andrea; Andreakos, Evangelos; Marr, Nico; Mentis, Alexios-Fotios; Mogensen, Trine Hyrup; Rodríguez-Gallego, Carlos; Soler-Palacín, Pere; Colobran, Roger; Tillmann, Vallo; Neven, Benedicte; Trouillet-Assant, Sophie; Brodin, Petter; Abel, Laurent; Jouanguy, Emmanuelle; Zhang, Qian; Martinon-Torres, Federico; Salas, Antonio; Gómez-Carballa, Alberto; Gonzalez-Granado, Luis Ignacio; Kisand, Kai; Okada, Satoshi; Puel, Anne; Cobat, Aurélie; Casanova, Jean-Laurent
    We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2.
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    Human genetic and immunological determinants of critical COVID-19 pneumonia
    (Springer Nature, 2022-03-24) Zhang, Qian; Bastard, Paul; Karbuz, Adem; Gervais, Adrian; Tayoun, Ahmad Abou; Aiuti, Alessandro; Belot, Alexandre; Bolze, Alexandre; Gaudet, Alexandre; Bondarenko, Anastasiia; Liu, Zhiyong; Spaan, András N.; Guennoun, Andrea; Arias, Andres Augusto; Planas, Anna M.; Sediva, Anna; Shcherbina, Anna; Neehus, Anna-Lena; Puel, Anne; Froidure, Antoine; Novelli, Antonio; Parlakay, Aslınur Özkaya; Pujol, Aurora; Yahşi, Aysun; Gülhan, Belgin; Bigio, Benedetta; Boisson, Bertrand; Drolet, Beth A.; Franco, Carlos Andres Arango; Flores, Carlos; Rodríguez-Gallego, Carlos; Prando, Carolina; Biggs, Catherine M.; Luyt, Charles-Edouard; Dalgard, Clifton L.; O’Farrelly, Cliona; Matuozzo, Daniela; Dalmau, David; Perlin, David S.; Mansouri, Davood; van de Beek, Diederik; Vinh, Donald C.; Dominguez-Garrido, Elena; Hsieh, Elena W. Y.; Erdeniz, Emine Hafize; Jouanguy, Emmanuelle; Şevketoglu, Esra; Talouarn, Estelle; Quiros-Roldan, Eugenia; Andreakos, Evangelos; Husebye, Eystein; Alsohime, Fahad; Haerynck, Filomeen; Casari, Giorgio; Novelli, Giuseppe; Aytekin, Gökhan; Morelle, Guillaume; Alkan, Gulsum; Bayhan, Gulsum Iclal; Feldman, Hagit Baris; Su, Helen C.; von Bernuth, Horst; Resnick, Igor; Bustos, Ingrid; Meyts, Isabelle; Migeotte, Isabelle; Tancevski, Ivan; Bustamante, Jacinta; Fellay, Jacques; El Baghdadi, Jamila; Martinez-Picado, Javier; Casanova, Jean-Laurent; Rosain, Jeremie; Manry, Jeremy; Chen, Jie; Christodoulou, John; Bohlen, Jonathan; Franco, José Luis; Li, Juan; Anaya, Juan Manuel; Rojas, Julian; Ye, Junqiang; Uddin, K. M. Furkan; Yasar, Kadriye Kart; Kisand, Kai; Okamoto, Keisuke; Chaïbi, Khalil; Mironska, Kristina; Maródi, László; Abel, Laurent; Renia, Laurent; Lorenzo, Lazaro; Hammarström, Lennart; Ng, Lisa F. P.; Quintana-Murci, Lluis; Erazo, Lucia Victoria; Notarangelo, Luigi D.; Reyes, Luis Felipe; Allende, Luis M.; Imberti, Luisa; Renkilaraj, Majistor Raj Luxman Maglorius; Moncada-Velez, Marcela; Materna, Marie; Anderson, Mark S.; Gut, Marta; Chbihi, Marwa; Ogishi, Masato; Emiroglu, Melike; Seppänen, Mikko R. J.; Uddin, Mohammed J.; Shahrooei, Mohammed; Alexander, Natalie; Hatipoglu, Nevin; Marr, Nico; Akçay, Nihal; Boyarchuk, Oksana; Slaby, Ondrej; Akcan, Ozge Metin; Zhang, Peng; Soler-Palacín, Pere; Gregersen, Peter K.; Brodin, Petter; Garçon, Pierre; Morange, Pierre-Emmanuel; Pan-Hammarström, Qiang; Zhou, Qinhua; Philippot, Quentin; Halwani, Rabih; de Diego, Rebeca Perez; Levy, Romain; Yang, Rui; Öz, Şadiye Kübra Tüter; Muhsen, Saleh Al; Kanık-Yüksek, Saliha; Espinosa-Padilla, Sara; Ramaswamy, Sathishkumar; Okada, Satoshi; Bozdemir, Sefika Elmas; Aytekin, Selma Erol; Karabela, Şemsi Nur; Keles, Sevgi; Senoglu, Sevtap; Zhang, Shen-Ying; Duvlis, Sotirija; Constantinescu, Stefan N.; Boisson-Dupuis, Stephanie; Turvey, Stuart E.; Tangye, Stuart G.; Asano, Takaki; Özcelik, Tayfun; Le Voyer, Tom; Maniatis, Tom; Morio, Tomohiro; Mogensen, Trine H.; Sancho-Shimizu, Vanessa; Beziat, Vivien; Solanich, Xavier; Bryceson, Yenan; Lau, Yu-Lung; Itan, Yuval; Cobat, Aurélie; Casanova, Jean-Laurent
    SARS-CoV-2 infection is benign in most individuals but, in around 10% of cases, it triggers hypoxaemic COVID-19 pneumonia, which leads to critical illness in around 3% of cases. The ensuing risk of death (approximately 1% across age and gender) doubles every five years from childhood onwards and is around 1.5 times greater in men than in women. Here we review the molecular and cellular determinants of critical COVID-19 pneumonia. Inborn errors of type I interferons (IFNs), including autosomal TLR3 and X-chromosome-linked TLR7 deficiencies, are found in around 1–5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing auto-antibodies neutralizing IFNα, IFNβ and/or IFNω, which are more common in men than in women, are found in approximately 15–20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defence against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation. © 2022, Springer Nature Limited.
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    Human TMEFF1 is a restriction factor for herpes simplex virus in the brain
    (NATURE PORTFOLIO, 2024-07) Chan, Yi-Hao; Liu, Zhiyong; Bastard, Paul; Khobrekar, Noopur; Hutchison, Kennen M.; Yamazaki, Yasuhiro; Fan, Qing; Matuozzo, Daniela; Harschnitz, Oliver; Kerrouche, Nacim; Nakajima, Koji; Amin, Param; Yatim, Ahmad; Rinchai, Darawan; Chen, Jie; Zhang, Peng; Ciceri, Gabriele; Chen, Jia; Dobbs, Kerry; Belkaya, Serkan; Lee, Danyel; Gervais, Adrian; Aydin, Kuersad; Kartal, Ayse; Hasek, Mary L.; Zhao, Shuxiang; Reino, Eduardo Garcia; Lee, Yoon Seung; Seeleuthner, Yoann; Chaldebas, Matthieu; Bailey, Rasheed; Vanhulle, Catherine; Lorenzo, Lazaro; Boucherit, Soraya; Rozenberg, Flore; Marr, Nico; Mogensen, Trine H.; Aubart, Melodie; Cobat, Aurelie; Dulac, Olivier; Emiroglu, Melike; Paludan, Soren R.; Abel, Laurent; Notarangelo, Luigi; Longnecker, Richard; Smith, Greg; Studer, Lorenz; Casanova, Jean-Laurent; Zhang, Shen-Ying
    Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE. A study of two childhood cases of herpes simplex encephalitis shows that TMEFF1 interacts with the HSV-1 cell-surface receptor NECTIN-1, preventing HSV-1 from fusing with the cell membrane and entering cortical neurons.
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    Respiratory viral infections in otherwise healthy humans with inherited IRF7 deficiency
    (Rockefeller University Press, 2022) Özçelik, Tayfun; Campbell, Tessa Mollie; Liu, Zhiyong; Zhang, Qian; Moncada-Velez, Marcela; Covill, Laura E.; Zhang, Peng; Darazam, Ilad Alavi; Bastard, Paul; Bizien, Lucy; Bucciol, Giorgia; Enoksson, Sara Lind; Jouanguy, Emmanuelle; Karabela, Şemsi Nur; Khan, Taushif; Kendir-Demirkol, Yasemin; Arias, Andres Augusto; Mansouri, Davood; Marits, Per; Marr, Nico; Migeotte, Isabelle; Moens, Leen; Pellier, Isabelle; Sendel, Anton; Shahrooei, Mohammad; Edvard Smith C.I.; Vandernoot, Isabelle; Willekens, Karen; Bergman, Peter; Abel, Laurent; Cobat, Aurélie; Casanova, Jean-Laurent; Meyts, Isabelle; Bryceson, Yenan T.
    Autosomal recessive IRF7 deficiency was previously reported in three patients with single critical influenza or COVID-19 pneumonia episodes. The patients’ fibroblasts and plasmacytoid dendritic cells produced no detectable type I and III IFNs, except IFN-β. Having discovered four new patients, we describe the genetic, immunological, and clinical features of seven IRF7-deficient patients from six families and five ancestries. Five were homozygous and two were compound heterozygous for IRF7 variants. Patients typically had one episode of pulmonary viral disease. Age at onset was surprisingly broad, from 6 mo to 50 yr (mean age 29 yr). The respiratory viruses implicated included SARS-CoV-2, influenza virus, respiratory syncytial virus, and adenovirus. Serological analyses indicated previous infections with many common viruses. Cellular analyses revealed strong antiviral immunity and expanded populations of influenza-and SARS-CoV-2–specific memory CD4+ and CD8+ Tcells. IRF7-deficient individuals are prone to viral infections of the respiratory tract but are otherwise healthy, potentially due to residual IFN-β and compensatory adaptive immunity. © 2022 Campbell et al.
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    SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency
    (Rockefeller University Press, 2024-07-18) Yi-Hao Chan; Lundberg, Vanja; Pen, Jérémie Le; Yuan, Jiayi; Lee, Danyel; Pinci, Francesca; Volpi, Stefano; Nakajima, Koji; Bondet, Vincent; Linnéa Åkesson, Sanna Emmy; Khobrekar, Noopur; 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; Prando, Carolina; Meyts, Isabelle; Wilson, Michael; Rosain, Jeremie; Jouanguy, Emmanuelle; Aubart, Melodie; Abel, Laurent; Mogensen, Trine Hyrup; Pan-Hammarström, Qiang; Gao, Daxing; Duffy, Darragh; Cobat, Aurélie; Berg, Stefan; Notarangelo, Luigi; Harschnitz, Oliver; Rice, Charles M.; Studer, Lorenz; Casanova, Jean-Laurent; Ekwall, Olov; Zhang, Shen-Ying
    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.
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    Studying severe long COVID to understand post-infectious disorders beyond COVID-19
    (Nature Publishing Group, 2022-05-01) Brodin, Petter; Casari, Giorgio; Townsend, Liam; O’Farrelly, Cliona; Tancevski, Ivan; Löffler-Ragg, Judith; Mogensen, Trine H.; Casanova, Jean Laurent; Abel, Laurent; Aiuti, Alessandro; Al-Muhsen, Saleh; Al-Mulla, Fahd; Anderson, Mark S.; Andreakos, Evangelos; Arias, Andrés A.; Feldman, HagitBaris; Belot, Alexandre; Biggs, Catherine M.; Bogunovic, Dusan; Bolze, Alexandre; Bondarenko, Anastasiia; Bousfiha, Ahmed A.; Bryceson, Yenan; Bustamante, Carlos D.; Butte, Manish J.; Christodoulou, John; Condino-Neto, Antonio; Constantinescu, Stefan N.; Cooper, Megan A.; Dalgard, Clifton L.; Desai, Murkesh; Drolet, Beth A.; Baghdadi, Jamila El; Espinosa-Padilla, Sara; Fellay, Jacques; Flores, Carlos; Franco, JoséLuis; Froidure, Antoine; Gregersen, Peter K.; Grimbacher, Bodo; Haerynck, Filomeen; Hagin, David; Halwani, Rabih; Hammarström, Lennart; Heath, James R.; Henrickson, Sarah E.; Hsieh, Elena W. Y.; Husebye, Eystein; Imai, Kohsuke; Itan, Yuval; Jarvis, Erich D.; Karamitros, Timokratis; Kisand, Kai; Ku, Cheng-Lung; Lau, Yu-Lung; Ling, Yun; Lucas, Carrie L.; Maniatis, Tom; Mansouri, Davood; Maródi, László; Meyts, Isabelle; Milner, Joshua D.; Mironska, Kristina; Morio, Tomohiro; Ng, Lisa F. P.; Novelli, Antonio; Novelli, Giuseppe; Okada, Satoshi; Okamoto, Keisuke; Ozcelik, Tayfun; Pan-Hammarström, Qiang; Pape, Jean W.; de Diego, Rebeca Perez; Perlin, David S.; Pesole, Graziano; Planas, Anna M.; Prando, Carolina; Pujol, Aurora; Quintana-Murci, Lluis; Ramaswamy, Sathishkumar; Renia, Laurent; Resnick, Igor; Rodríguez-Gallego, Carlos; Sancho-Shimizu, Vanessa; Sediva, Anna; Seppänen, Mikko R. J.; Shahrooei, Mohammed; Shcherbina, Anna; Slaby, Ondrej; Snow, Andrew L.; Soler-Palacín, Pere; Spaan, András N.; Tangye, Stuart G.; Tayoun, Ahmad Abou; Turvey, Stuart E.; Uddin, K. M. Furkan; Uddin, Mohammed J.; vande Beek, Diederik; Vinh, Donald C.; von Bernuth, Horst; Wauters, Joost; Zatz, Mayana; Zawadzki, Pawel; Casanova, Jean-Laurent