Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

• Published in: Cell 2023-02, Vol.186 (3), p.621-645.e33
• Main Authors: Rosain, Jérémie, Neehus, Anna-Lena, Manry, Jérémy, Yang, Rui, Le Pen, Jérémie, Daher, Wassim, Liu, Zhiyong, Chan, Yi-Hao, Tahuil, Natalia, Türel, Özden, Bourgey, Mathieu, Ogishi, Masato, Doisne, Jean-Marc, Izquierdo, Helena M., Shirasaki, Takayoshi, Le Voyer, Tom, Guérin, Antoine, Bastard, Paul, Moncada-Vélez, Marcela, Han, Ji Eun, Khan, Taushif, Rapaport, Franck, Hong, Seon-Hui, Cheung, Andrew, Haake, Kathrin, Mindt, Barbara C., Pérez, Laura, Philippot, Quentin, Lee, Danyel, Zhang, Peng, Rinchai, Darawan, Al Ali, Fatima, Ahmad Ata, Manar Mahmoud, Rahman, Mahbuba, Peel, Jessica N., Heissel, Søren, Molina, Henrik, Kendir-Demirkol, Yasemin, Bailey, Rasheed, Zhao, Shuxiang, Bohlen, Jonathan, Mancini, Mathieu, Seeleuthner, Yoann, Roelens, Marie, Lorenzo, Lazaro, Soudée, Camille, Paz, María Elvira Josefina, González, María Laura, Jeljeli, Mohamed, Soulier, Jean, Romana, Serge, L’Honneur, Anne-Sophie, Materna, Marie, Martínez-Barricarte, Rubén, Pochon, Mathieu, Oleaga-Quintas, Carmen, Michev, Alexandre, Migaud, Mélanie, Lévy, Romain, Alyanakian, Marie-Alexandra, Rozenberg, Flore, Croft, Carys A., Vogt, Guillaume, Emile, Jean-François, Kremer, Laurent, Ma, Cindy S., Fritz, Jörg H., Lemon, Stanley M., Spaan, András N., Manel, Nicolas, Abel, Laurent, MacDonald, Margaret R., Boisson-Dupuis, Stéphanie, Marr, Nico, Tangye, Stuart G., Di Santo, James P., Zhang, Qian, Zhang, Shen-Ying, Rice, Charles M., Béziat, Vivien, Lachmann, Nico, Langlais, David, Casanova, Jean-Laurent, Gros, Philippe, Bustamante, Jacinta
• Format: Article
• Language: English
• Subjects: Child; COVID-19; Humans; inborn errors of immunity; Interferon Regulatory Factor-1; Interferon-alpha; Interferon-gamma; interferon-stimulated gene; interferon-γ; IRF1; Life Sciences; macrophages; Mycobacterium; SARS-CoV-2; viruses
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2022.12.038

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity. [Display omitted] •Inherited complete human IRF1 deficiency underlies severe mycobacterial disease•Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria•Human IRF1 is essential for IFN-γ- and STAT1-dependent immunity to mycobacteria•Human IRF1 is largely redundant for IFN-α/β-dependent antiviral intrinsic immunity Studies in humans with interferon regulatory factor 1 (IRF1) deficiency reveal differences in how type I and type II interferons protect humans against different types of pathogens.