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

Author

Chan, Yi-Hao, Lundberg, Vanja, Le Pen, Jérémie, Yuan, Jiayi, Lee, Danyel, Pinci, Francesca, Volpi, Stefano, Nakajima, Koji, Bondet, Vincent, Åkesson, Sanna, Khobrekar, Noopur, Bodansky, Aaron, Du, Likun, Melander, Tina, Mariaggi, Alice-Andrée, Seeleuthner, Yoann, Saleh, Tariq, 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, Jérémie, Jouanguy, Emmanuelle, Aubart, Mélodie, Abel, Laurent, Mogensen, Trine, Pan-Hammarström, Qiang, Gao, Daxing, Duffy, Darragh, Cobat, Aurélie, Berg, Stefan, Notarangelo, Luigi, Harschnitz, Oliver, Rice, Charles, Studer, Lorenz, Casanova, Jean-Laurent, Ekwall, Olov, and Zhang, Shen-Ying

Subjects
Humans, Male, SARS-CoV-2, COVID-19, Brain Stem, Adolescent, Neurons, Encephalitis, Viral, Fibroblasts, Rhombencephalon
Abstract

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.

Published
2024

2. Tuberculosis in otherwise healthy adults with inherited TNF deficiency

Author

Arias, Andrés A., Neehus, Anna-Lena, Ogishi, Masato, Meynier, Vincent, Krebs, Adam, Lazarov, Tomi, Lee, Angela M., Arango-Franco, Carlos A., Yang, Rui, Orrego, Julio, Corcini Berndt, Melissa, Rojas, Julian, Li, Hailun, Rinchai, Darawan, Erazo-Borrás, Lucia, Han, Ji Eun, Pillay, Bethany, Ponsin, Khoren, Chaldebas, Matthieu, Philippot, Quentin, Bohlen, Jonathan, Rosain, Jérémie, Le Voyer, Tom, Janotte, Till, Amarajeeva, Krishnajina, Soudée, Camille, Brollo, Marion, Wiegmann, Katja, Marquant, Quentin, Seeleuthner, Yoann, Lee, Danyel, Lainé, Candice, Kloos, Doreen, Bailey, Rasheed, Bastard, Paul, Keating, Narelle, Rapaport, Franck, Khan, Taushif, Moncada-Vélez, Marcela, Carmona, María Camila, Obando, Catalina, Alvarez, Jesús, Cataño, Juan Carlos, Martínez-Rosado, Larry Luber, Sanchez, Juan P., Tejada-Giraldo, Manuela, L’Honneur, Anne-Sophie, Agudelo, María L., Perez-Zapata, Lizet J., Arboleda, Diana M., Alzate, Juan Fernando, Cabarcas, Felipe, Zuluaga, Alejandra, Pelham, Simon J., Ensser, Armin, Schmidt, Monika, Velásquez-Lopera, Margarita M., Jouanguy, Emmanuelle, Puel, Anne, Krönke, Martin, Ghirardello, Stefano, Borghesi, Alessandro, Pahari, Susanta, Boisson, Bertrand, Pittaluga, Stefania, Ma, Cindy S., Emile, Jean-François, Notarangelo, Luigi D., Tangye, Stuart G., Marr, Nico, Lachmann, Nico, Salvator, Hélène, Schlesinger, Larry S., Zhang, Peng, Glickman, Michael S., Nathan, Carl F., Geissmann, Frédéric, Abel, Laurent, Franco, José Luis, Bustamante, Jacinta, Casanova, Jean-Laurent, and Boisson-Dupuis, Stéphanie

Published
2024
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3. Human TMEFF1 is a restriction factor for herpes simplex virus in the brain

Author

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, Aydın, Kürşad, 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, Mélodie, Cobat, Aurélie, Dulac, Olivier, Emiroglu, Melike, Paludan, Søren R., Abel, Laurent, Notarangelo, Luigi, Longnecker, Richard, Smith, Greg, Studer, Lorenz, Casanova, Jean-Laurent, and Zhang, Shen-Ying

Published
2024
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4. Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Author

Matuozzo, Daniela, Talouarn, Estelle, Marchal, Astrid, Zhang, Peng, Manry, Jeremy, Seeleuthner, Yoann, Zhang, Yu, Bolze, Alexandre, Chaldebas, Matthieu, Milisavljevic, Baptiste, Gervais, Adrian, Bastard, Paul, Asano, Takaki, Bizien, Lucy, Barzaghi, Federica, Abolhassani, Hassan, Tayoun, Ahmad Abou, Aiuti, Alessandro, Darazam, Ilad Alavi, Allende, Luis M., Alonso-Arias, Rebeca, Arias, Andrés Augusto, Aytekin, Gokhan, Bergman, Peter, Bondesan, Simone, Bryceson, Yenan T., Bustos, Ingrid G., Cabrera-Marante, Oscar, Carcel, Sheila, Carrera, Paola, Casari, Giorgio, Chaïbi, Khalil, Colobran, Roger, Condino-Neto, Antonio, Covill, Laura E., Delmonte, Ottavia M., Zein, Loubna El, Flores, Carlos, Gregersen, Peter K., Gut, Marta, Haerynck, Filomeen, Halwani, Rabih, Hancerli, Selda, Hammarström, Lennart, Hatipoğlu, Nevin, Karbuz, Adem, Keles, Sevgi, Kyheng, Christèle, Leon-Lopez, Rafael, Franco, Jose Luis, Mansouri, Davood, Martinez-Picado, Javier, Akcan, Ozge Metin, Migeotte, Isabelle, Morange, Pierre-Emmanuel, Morelle, Guillaume, Martin-Nalda, Andrea, Novelli, Giuseppe, Novelli, Antonio, Ozcelik, Tayfun, Palabiyik, Figen, Pan-Hammarström, Qiang, de Diego, Rebeca Pérez, Planas-Serra, Laura, Pleguezuelo, Daniel E., Prando, Carolina, Pujol, Aurora, Reyes, Luis Felipe, Rivière, Jacques G., Rodriguez-Gallego, Carlos, Rojas, Julian, Rovere-Querini, Patrizia, Schlüter, Agatha, Shahrooei, Mohammad, Sobh, Ali, Soler-Palacin, Pere, Tandjaoui-Lambiotte, Yacine, Tipu, Imran, Tresoldi, Cristina, Troya, Jesus, van de Beek, Diederik, Zatz, Mayana, Zawadzki, Pawel, Al-Muhsen, Saleh Zaid, Alosaimi, Mohammed Faraj, Alsohime, Fahad M., Baris-Feldman, Hagit, Butte, Manish J., Constantinescu, Stefan N., Cooper, Megan A., Dalgard, Clifton L., Fellay, Jacques, Heath, James R., Lau, Yu-Lung, Lifton, Richard P., Maniatis, Tom, Mogensen, Trine H., von Bernuth, Horst, Lermine, Alban, Vidaud, Michel, Boland, Anne, Deleuze, Jean-François, Nussbaum, Robert, Kahn-Kirby, Amanda, Mentre, France, Tubiana, Sarah, Gorochov, Guy, Tubach, Florence, Hausfater, Pierre, Meyts, Isabelle, Zhang, Shen-Ying, Puel, Anne, Notarangelo, Luigi D., Boisson-Dupuis, Stephanie, Su, Helen C., Boisson, Bertrand, Jouanguy, Emmanuelle, Casanova, Jean-Laurent, Zhang, Qian, Abel, Laurent, and Cobat, Aurélie

Published
2024
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5. Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Author

Matuozzo, Daniela, Talouarn, Estelle, Marchal, Astrid, Zhang, Peng, Manry, Jeremy, Seeleuthner, Yoann, Zhang, Yu, Bolze, Alexandre, Chaldebas, Matthieu, Milisavljevic, Baptiste, Gervais, Adrian, Bastard, Paul, Asano, Takaki, Bizien, Lucy, Barzaghi, Federica, Abolhassani, Hassan, Abou Tayoun, Ahmad, Aiuti, Alessandro, Alavi Darazam, Ilad, Allende, Luis M, Alonso-Arias, Rebeca, Arias, Andrés Augusto, Aytekin, Gokhan, Bergman, Peter, Bondesan, Simone, Bryceson, Yenan T, Bustos, Ingrid G, Cabrera-Marante, Oscar, Carcel, Sheila, Carrera, Paola, Casari, Giorgio, Chaïbi, Khalil, Colobran, Roger, Condino-Neto, Antonio, Covill, Laura E, Delmonte, Ottavia M, El Zein, Loubna, Flores, Carlos, Gregersen, Peter K, Gut, Marta, Haerynck, Filomeen, Halwani, Rabih, Hancerli, Selda, Hammarström, Lennart, Hatipoğlu, Nevin, Karbuz, Adem, Keles, Sevgi, Kyheng, Christèle, Leon-Lopez, Rafael, Franco, Jose Luis, Mansouri, Davood, Martinez-Picado, Javier, Metin Akcan, Ozge, Migeotte, Isabelle, Morange, Pierre-Emmanuel, Morelle, Guillaume, Martin-Nalda, Andrea, Novelli, Giuseppe, Novelli, Antonio, Ozcelik, Tayfun, Palabiyik, Figen, Pan-Hammarström, Qiang, de Diego, Rebeca Pérez, Planas-Serra, Laura, Pleguezuelo, Daniel E, Prando, Carolina, Pujol, Aurora, Reyes, Luis Felipe, Rivière, Jacques G, Rodriguez-Gallego, Carlos, Rojas, Julian, Rovere-Querini, Patrizia, Schlüter, Agatha, Shahrooei, Mohammad, Sobh, Ali, Soler-Palacin, Pere, Tandjaoui-Lambiotte, Yacine, Tipu, Imran, Tresoldi, Cristina, Troya, Jesus, van de Beek, Diederik, Zatz, Mayana, Zawadzki, Pawel, Al-Muhsen, Saleh Zaid, Alosaimi, Mohammed Faraj, Alsohime, Fahad M, Baris-Feldman, Hagit, Butte, Manish J, Constantinescu, Stefan N, Cooper, Megan A, Dalgard, Clifton L, Fellay, Jacques, Heath, James R, Lau, Yu-Lung, Lifton, Richard P, Maniatis, Tom, Mogensen, Trine H, von Bernuth, Horst, Lermine, Alban, and Vidaud, Michel

Subjects
Clinical Research, Infectious Diseases, Pneumonia & Influenza, Genetics, Human Genome, Prevention, 2.1 Biological and endogenous factors, Aetiology, Humans, Young Adult, Adult, Middle Aged, COVID-19, SARS-CoV-2, Toll-Like Receptor 3, Toll-Like Receptor 7, Interferon Type I, Autoantibodies, COVID Human Genetic Effort, COVIDeF Study Group, French COVID Cohort Study Group, CoV-Contact Cohort, COVID-STORM Clinicians, COVID Clinicians, Orchestra Working Group, Amsterdam UMC Covid-19 Biobank, NIAID-USUHS COVID Study Group, Immunity, Rare variants, Type I interferon, Clinical Sciences
Abstract

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P = 1.1 × 10-4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3-8.2], P = 2.1 × 10-4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1-2635.4], P = 3.4 × 10-3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3-8.4], P = 7.7 × 10-8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10-5).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Published
2023

6. Genome-wide detection of human intronic AG-gain variants located between splicing branchpoints and canonical splice acceptor sites

Author

Zhang, Peng, primary, Chaldebas, Matthieu, additional, Ogishi, Masato, additional, Al Qureshah, Fahd, additional, Ponsin, Khoren, additional, Feng, Yi, additional, Rinchai, Darawan, additional, Milisavljevic, Baptiste, additional, Han, Ji Eun, additional, Moncada-Vélez, Marcela, additional, Keles, Sevgi, additional, Schröder, Bernd, additional, Stenson, Peter D., additional, Cooper, David N., additional, Cobat, Aurélie, additional, Boisson, Bertrand, additional, Zhang, Qian, additional, Boisson-Dupuis, Stéphanie, additional, Abel, Laurent, additional, and Casanova, Jean-Laurent, additional

Published
2023
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7. OC 9 - HOMOZYGOUS CBL MUTATION IN B LYMPHOCYTES AFTER CBL-DRIVEN JMML IMPAIRS B CELL MATURATION, FUNCTION AND ANTIBACTERIAL IMMUNITY

Author

Bohlen, Jonathan, Michelet, Marine, Barzaghi, Federica, Saettini, Francesco, Vendemini, Francesca, Catala, Albert, Alsina, Laia, Conti, Francesca, Consonni, Fillippo, Learndini, Davide, Masetti, Riccardo, Muratore, Edoardo, Baccelli, Francesco, Bagaric, Ivan, Vatovec, Taja, Seyed, Feroj, Andre, Isabelle, Buetow, Lori, Delabesse, Eric, Largeaud, Laetitia, Ma, Cindy, Abel, Laurent, Sobrino, Steicy, Ogishi, Masato, Bessot, Boris, Rouillon, Cecile, Bole, Christine, Seeleuthner, Yoann, Voyer, Tom Le, Rinchai, Darawan, Rosain, Jeremie, Zhang, Peng, Chaldebas, Matthieu, Neehus, Anna-Lena, Erazo, Lucia, Janda, Zarah, Soudee, Camille, Lagrese, Chantal, Six, Emmanuelle, Huang, Danny, Tangye, Stuart, Beziat, Vivien, Gambineri, Eleonora, Veltroni, Marinella, Erlacher, Miriam, Aiuti, Alessandro, Pasquet, Marlene, Casanova, Jean-Laurent, and Bustamante, Jacinta

Published
2023
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8. Genome-wide detection of human intronic AG-gain variants located between splicing branchpoints and canonical splice acceptor sites.

Author

Peng Zhang, Chaldebas, Matthieu, Ogishi, Masato, Al Qureshah, Fahd, Ponsin, Khoren, Yi Feng, Rinchai, Darawan, Milisavljevic, Baptiste, Ji Eun Han, Moncada-Vélez, Marcela, Keles, Sevgi, Schröder, Bernd, Stenson, Peter D., Cooper, David N., Cobat, Aurélie, Boisson, Bertrand, Qian Zhang, Boisson-Dupuis, Stéphanie, Abel, Laurent, and Casanova, Jean-Laurent

Subjects
*GENETIC variation, *MYCOBACTERIAL diseases, *DATABASES, *HUMAN genetics, *GENETIC mutation
Abstract

Human genetic variants that introduce an AG into the intronic region between the branchpoint (BP) and the canonical splice acceptor site (ACC) of protein-coding genes can disrupt pre-mRNA splicing. Using our genome-wide BP database, we delineated the BP-ACC segments of all human introns and found extreme depletion of AG/YAG in the [BP+8, ACC-4] high-risk region. We developed AGAIN as a genome-wide computational approach to systematically and precisely pinpoint intronic AG-gain variants within the BP-ACC regions. AGAIN identified 350 AG-gain variants from the Human Gene Mutation Database, all of which alter splicing and cause disease. Among them, 74% created new acceptor sites, whereas 31% resulted in complete exon skipping. AGAIN also predicts the protein-level products resulting from these two consequences. We performed AGAIN on our exome/genomes database of patients with severe infectious diseases but without known genetic etiology and identified a private homozygous intronic AG-gain variant in the antimycobacterial gene SPPL2A in a patient with mycobacterial disease. AGAIN also predicts a retention of six intronic nucleotides that encode an in-frame stop codon, turning AG-gain into stop-gain. This allele was then confirmed experimentally to lead to loss of function by disrupting splicing. We further showed that AG-gain variants inside the high-risk region led to misspliced products, while those outside the region did not, by two case studies in genes STAT1 and IRF7. We finally evaluated AGAIN on our 14 paired exome-RNAseq samples and found that 82% of AG-gain variants in high-risk regions showed evidence of missplicing. [ABSTRACT FROM AUTHOR]

Published
2023
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9. Additional file 1 of Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Author

Matuozzo, Daniela, Talouarn, Estelle, Marchal, Astrid, Zhang, Peng, Manry, Jeremy, Seeleuthner, Yoann, Zhang, Yu, Bolze, Alexandre, Chaldebas, Matthieu, Milisavljevic, Baptiste, Gervais, Adrian, Bastard, Paul, Asano, Takaki, Bizien, Lucy, Barzaghi, Federica, Abolhassani, Hassan, Abou Tayoun, Ahmad, Aiuti, Alessandro, Alavi Darazam, Ilad, Allende, Luis M., Alonso-Arias, Rebeca, Arias, Andrés Augusto, Aytekin, Gokhan, Bergman, Peter, Bondesan, Simone, Bryceson, Yenan T., Bustos, Ingrid G., Cabrera-Marante, Oscar, Carcel, Sheila, Carrera, Paola, Casari, Giorgio, Chaïbi, Khalil, Colobran, Roger, Condino-Neto, Antonio, Covill, Laura E., Delmonte, Ottavia M., El Zein, Loubna, Flores, Carlos, Gregersen, Peter K., Gut, Marta, Haerynck, Filomeen, Halwani, Rabih, Hancerli, Selda, Hammarström, Lennart, Hatipoğlu, Nevin, Karbuz, Adem, Keles, Sevgi, Kyheng, Christèle, Leon-Lopez, Rafael, Franco, Jose Luis, Mansouri, Davood, Martinez-Picado, Javier, Metin Akcan, Ozge, Migeotte, Isabelle, Morange, Pierre-Emmanuel, Morelle, Guillaume, Martin-Nalda, Andrea, Novelli, Giuseppe, Novelli, Antonio, Ozcelik, Tayfun, Palabiyik, Figen, Pan-Hammarström, Qiang, de Diego, Rebeca Pérez, Planas-Serra, Laura, Pleguezuelo, Daniel E., Prando, Carolina, Pujol, Aurora, Reyes, Luis Felipe, Rivière, Jacques G., Rodriguez-Gallego, Carlos, Rojas, Julian, Rovere-Querini, Patrizia, Schlüter, Agatha, Shahrooei, Mohammad, Sobh, Ali, Soler-Palacin, Pere, Tandjaoui-Lambiotte, Yacine, Tipu, Imran, Tresoldi, Cristina, Troya, Jesus, van de Beek, Diederik, Zatz, Mayana, Zawadzki, Pawel, Al-Muhsen, Saleh Zaid, Alosaimi, Mohammed Faraj, Alsohime, Fahad M., Baris-Feldman, Hagit, Butte, Manish J., Constantinescu, Stefan N., Cooper, Megan A., Dalgard, Clifton L., Fellay, Jacques, Heath, James R., Lau, Yu-Lung, Lifton, Richard P., Maniatis, Tom, Mogensen, Trine H., von Bernuth, Horst, Lermine, Alban, Vidaud, Michel, Boland, Anne, Deleuze, Jean-François, Nussbaum, Robert, Kahn-Kirby, Amanda, Mentre, France, Tubiana, Sarah, Gorochov, Guy, Tubach, Florence, Hausfater, Pierre, Meyts, Isabelle, Zhang, Shen-Ying, Puel, Anne, Notarangelo, Luigi D., Boisson-Dupuis, Stephanie, Su, Helen C., Boisson, Bertrand, Jouanguy, Emmanuelle, Casanova, Jean-Laurent, Zhang, Qian, Abel, Laurent, and Cobat, Aurélie

Abstract

Additional file 1: Supplementary Methods. Fig S1. Luciferase assay on HEK293T cells transfected with the pGL4.32 luciferase reporter construct and an expression vector for Renilla luciferase together with no vector (mock), EV, WT, or 4 TLR7 variants found in our cohort. After 24 h, transfected cells were left untreated or were treated by incubation with 1 μg/mL R848 for 24 h. These data were established from two independent experiments. The y-axis represents NF-κB transcriptional activity as a percentage of the WT. The x-axis indicates the alleles used for transfection. Fig S2. Age distribution as boxplot and violin plot of the critical COVID-19 cases according to the carrier status of pLOF/bLOF at 15 type I IFN-related loci. Mean age of the patients for each category is shown in red. T-test was used to compare the means, showing a significant difference between non-carriers and carriers of heterozygous or homozygous/hemizygous variants (P = 2.2 × 10−6) and between heterozygous carriers and homozygous/hemizygous carriers (P = 0.008). Fig S3. Empirical power of our sample to detect an association at the 2.5 × 10−6 exome-wide significance threshold for various relative risks and proportion of carriers of at least one disease causing variant in the general population (PD), as estimated by simulation study (N = 1000 replicates).

Published
2023
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10. IL-7-dependent and -independent lineages of IL-7R-dependent human T cells.

Author

Arango-Franco CA, Ogishi M, Unger S, Delmonte OM, Orrego JC, Yatim A, Velasquez-Lopera MM, Zea-Vera AF, Bohlen J, Chbihi M, Fayand A, Sánchez JP, Rojas J, Seeleuthner Y, Le Voyer T, Philippot Q, Payne KJ, Gervais A, Erazo-Borrás LV, Correa-Londoño LA, Cederholm A, Gallón-Duque A, Goncalves P, Doisne JM, Horev L, Charmeteau-de Muylder B, Álvarez JÁ, Arboleda DM, Pérez-Zapata L, Vásquez-Echeverri E, Moncada-Vélez M, López JA, Caicedo Y, Palterer B, Patiño PJ, Montoya CJ, Chaldebas M, Zhang P, Nguyen T, Ma CS, Jeljeli M, Alzate JF, Cabarcas F, Khan T, Rinchai D, Prétet JL, Boisson B, Marr N, Ibrahim R, Molho-Pessach V, Boisson-Dupuis S, Kiritsi D, Barata JT, Landegren N, Neven B, Abel L, Lisco A, Béziat V, Jouanguy E, Bustamante J, Di Santo JP, Tangye SG, Notarangelo LD, Cheynier R, Natsuga K, Arias AA, Franco JL, Warnatz K, Casanova JL, and Puel A

Subjects
Humans, Adult, Male, Female, Middle Aged, Severe Combined Immunodeficiency immunology, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency pathology, Cell Lineage immunology, T-Lymphocytes immunology, Interleukin-7 Receptor alpha Subunit, Interleukin-7 immunology, Interleukin-7 genetics, Interleukin-7 metabolism, Receptors, Interleukin-7 genetics, Receptors, Interleukin-7 immunology, Receptors, Interleukin-7 metabolism
Abstract

Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T-B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαβ+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development.

Published
2024
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12. Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.

Author

Matuozzo D, Talouarn E, Marchal A, Manry J, Seeleuthner Y, Zhang Y, Bolze A, Chaldebas M, Milisavljevic B, Zhang P, Gervais A, Bastard P, Asano T, Bizien L, Barzaghi F, Abolhassani H, Tayoun AA, Aiuti A, Darazam IA, Allende LM, Alonso-Arias R, Arias AA, Aytekin G, Bergman P, Bondesan S, Bryceson YT, Bustos IG, Cabrera-Marante O, Carcel S, Carrera P, Casari G, Chaïbi K, Colobran R, Condino-Neto A, Covill LE, El Zein L, Flores C, Gregersen PK, Gut M, Haerynck F, Halwani R, Hancerli S, Hammarström L, Hatipoğlu N, Karbuz A, Keles S, Kyheng C, Leon-Lopez R, Franco JL, Mansouri D, Martinez-Picado J, Akcan OM, Migeotte I, Morange PE, Morelle G, Martin-Nalda A, Novelli G, Novelli A, Ozcelik T, Palabiyik F, Pan-Hammarström Q, Pérez de Diego R, Planas-Serra L, Pleguezuelo DE, Prando C, Pujol A, Reyes LF, Rivière JG, Rodriguez-Gallego C, Rojas J, Rovere-Querini P, Schlüter A, Shahrooei M, Sobh A, Soler-Palacin P, Tandjaoui-Lambiotte Y, Tipu I, Tresoldi C, Troya J, van de Beek D, Zatz M, Zawadzki P, Al-Muhsen SZ, Baris-Feldman H, Butte MJ, Constantinescu SN, Cooper MA, Dalgard CL, Fellay J, Heath JR, Lau YL, Lifton RP, Maniatis T, Mogensen TH, von Bernuth H, Lermine A, Vidaud M, Boland A, Deleuze JF, Nussbaum R, Kahn-Kirby A, Mentre F, Tubiana S, Gorochov G, Tubach F, Hausfater P, Meyts I, Zhang SY, Puel A, Notarangelo LD, Boisson-Dupuis S, Su HC, Boisson B, Jouanguy E, Casanova JL, Zhang Q, Abel L, and Cobat A

Abstract

Background: We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases., Methods: We report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis., Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7 , with an OR of 27.68 (95%CI:1.5-528.7, P= 1.1×10 -4 ), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2], P= 2.1×10 -4 ). Adding the recently reported TYK2 COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; P= 3.4×10 -3 ). When these 14 loci and TLR7 were considered, all individuals hemizygous ( n =20) or homozygous ( n =5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], P =4.7×10 -7 ), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], P =0.02). Finally, the patients with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P= 1.68×10 -5 )., Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Published
2022
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