Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Jérémie Rosain; Anna-Lena Neehus; Jérémy Manry; Rui Yang; Jérémie Le Pen; Wassim Daher; Zhiyong Liu; Yi-Hao Chan; Natalia Tahuil; Özden Türel; Mathieu Bourgey; Masato Ogishi; Jean-Marc Doisne; Helena M Izquierdo; Takayoshi Shirasaki; Tom Le Voyer; Antoine Guérin; Paul Bastard; Marcela Moncada-Vélez; Ji Eun Han; Taushif Khan; Franck Rapaport; Seon-Hui Hong; Andrew Cheung; Kathrin Haake; Barbara C Mindt; Laura Pérez; Quentin Philippot; Danyel Lee; Peng Zhang; Darawan Rinchai; Fatima Al Ali; Manar Mahmoud Ahmad Ata; Mahbuba Rahman; Jessica N Peel; Søren Heissel; Henrik Molina; Yasemin Kendir-Demirkol; Rasheed Bailey; Shuxiang Zhao; Jonathan Bohlen; Mathieu Mancini; Yoann Seeleuthner; Marie Roelens; Lazaro Lorenzo; Camille Soudée; María Elvira Josefina Paz; María Laura González; Mohamed Jeljeli; Jean Soulier; Serge Romana; Anne-Sophie L'Honneur; Marie Materna; Rubén Martínez-Barricarte; Mathieu Pochon; Carmen Oleaga-Quintas; Alexandre Michev; Mélanie Migaud; Romain Lévy; Marie-Alexandra Alyanakian; Flore Rozenberg; Carys A Croft; Guillaume Vogt; Jean-François Emile; Laurent Kremer; Cindy S Ma; Jörg H Fritz; Stanley M Lemon; András N Spaan; Nicolas Manel; Laurent Abel; Margaret R MacDonald; Stéphanie Boisson-Dupuis; Nico Marr; Stuart G Tangye; James P Di Santo; Qian Zhang; Shen-Ying Zhang; Charles M Rice; Vivien Béziat; Nico Lachmann; David Langlais; Jean-Laurent Casanova; Philippe Gros; Jacinta Bustamante

doi:10.1016/j.cell.2022.12.038

Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Cell. 2023 Feb 2;186(3):621-645.e33. doi: 10.1016/j.cell.2022.12.038.

Authors

Jérémie Rosain¹, Anna-Lena Neehus², Jérémy Manry³, Rui Yang⁴, Jérémie Le Pen⁵, Wassim Daher⁶, Zhiyong Liu⁴, Yi-Hao Chan⁴, Natalia Tahuil⁷, Özden Türel⁸, Mathieu Bourgey⁹, Masato Ogishi⁴, Jean-Marc Doisne¹⁰, Helena M Izquierdo¹¹, Takayoshi Shirasaki¹², Tom Le Voyer¹³, Antoine Guérin¹⁴, Paul Bastard¹⁵, Marcela Moncada-Vélez⁴, Ji Eun Han⁴, Taushif Khan¹⁶, Franck Rapaport⁴, Seon-Hui Hong⁵, Andrew Cheung⁵, Kathrin Haake¹⁷, Barbara C Mindt¹⁸, Laura Pérez¹⁹, Quentin Philippot¹³, Danyel Lee²⁰, Peng Zhang⁴, Darawan Rinchai⁴, Fatima Al Ali¹⁶, Manar Mahmoud Ahmad Ata¹⁶, Mahbuba Rahman¹⁶, Jessica N Peel⁴, Søren Heissel²¹, Henrik Molina²¹, Yasemin Kendir-Demirkol²², Rasheed Bailey⁴, Shuxiang Zhao⁴, Jonathan Bohlen¹³, Mathieu Mancini²³, Yoann Seeleuthner¹³, Marie Roelens²⁴, Lazaro Lorenzo¹³, Camille Soudée¹³, María Elvira Josefina Paz²⁵, María Laura González²⁶, Mohamed Jeljeli²⁷, Jean Soulier²⁸, Serge Romana²⁹, Anne-Sophie L'Honneur³⁰, Marie Materna¹³, Rubén Martínez-Barricarte³¹, Mathieu Pochon¹³, Carmen Oleaga-Quintas¹³, Alexandre Michev¹³, Mélanie Migaud¹³, Romain Lévy³², Marie-Alexandra Alyanakian³³, Flore Rozenberg³⁰, Carys A Croft³⁴, Guillaume Vogt³⁵, Jean-François Emile³⁶, Laurent Kremer⁶, Cindy S Ma¹⁴, Jörg H Fritz³⁷, Stanley M Lemon¹², András N Spaan³⁸, Nicolas Manel¹¹, Laurent Abel²⁰, Margaret R MacDonald⁵, Stéphanie Boisson-Dupuis²⁰, Nico Marr³⁹, Stuart G Tangye¹⁴, James P Di Santo¹⁰, Qian Zhang²⁰, Shen-Ying Zhang²⁰, Charles M Rice⁵, Vivien Béziat²⁰, Nico Lachmann⁴⁰, David Langlais⁴¹, Jean-Laurent Casanova⁴², Philippe Gros⁴³, Jacinta Bustamante⁴⁴

Affiliations

¹ Laboratory of Human Genetics of Infectious Diseases, Inserm U1163, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France. Electronic address: jeremie.rosain@institutimagine.org.
² Laboratory of Human Genetics of Infectious Diseases, Inserm U1163, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; Institute of Experimental Hematology, REBIRTH Center for Regenerative and Translational Medicine, Hannover Medical School, 30625 Hannover, Germany.
³ Laboratory of Human Genetics of Infectious Diseases, Inserm U1163, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France.
⁴ St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
⁵ Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
⁶ Infectious Disease Research Institute of Montpellier (IRIM), Montpellier University, 34090 Montpellier, France; Inserm, IRIM, CNRS, UMR9004, 34090 Montpellier, France.
⁷ Department of Immunology, Del Niño Jesus Hospital, San Miguel de Tucuman, T4000 Tucuman, Argentina.
⁸ Department of Pediatric Infectious Disease, Bezmialem Vakif University Faculty of Medicine, 34093 İstanbul, Turkey.
⁹ Dahdaleh Institute of Genomic Medicine, McGill University, Montreal, QC H3A 0G1, Canada; Canadian Centre for Computation Genomics, Montreal, QC H3A 0G1, Canada.
¹⁰ Innate Immunity Unit, Institut Pasteur, 75015 Paris, France; Inserm U1223, 75015 Paris, France.
¹¹ Institut Curie, PSL Research University, Inserm U932, 75005 Paris, France.
¹² Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7292, USA.
¹³ Laboratory of Human Genetics of Infectious Diseases, Inserm U1163, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France.
¹⁴ Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2052, Australia.
¹⁵ Laboratory of Human Genetics of Infectious Diseases, Inserm U1163, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA; Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique Hôpitaux de Paris (AP-HP), 75015 Paris, France.
¹⁶ Department of Immunology, Sidra Medicine, Doha, Qatar.
¹⁷ Institute of Experimental Hematology, REBIRTH Center for Regenerative and Translational Medicine, Hannover Medical School, 30625 Hannover, Germany.
¹⁸ Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 0G1, Canada; McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3A 0G1, Canada; FOCiS Centre of Excellence in Translational Immunology, McGill University, Montreal, QC H3A 0G1, Canada.
¹⁹ Department of Immunology and Rheumatology, "J. P. Garrahan" National Hospital of Pediatrics, C1245 CABA Buenos Aires, Argentina.
²⁰ Laboratory of Human Genetics of Infectious Diseases, Inserm U1163, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
²¹ Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
²² St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA; Umraniye Education and Research Hospital, Department of Pediatric Genetics, 34764 İstanbul, Turkey.
²³ Dahdaleh Institute of Genomic Medicine, McGill University, Montreal, QC H3A 0G1, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 0G1, Canada; McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3A 0G1, Canada.
²⁴ Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France; Paris Cité University, 75006 Paris, France.
²⁵ Department of Pediatric Pathology, Del Niño Jesus Hospital, San Miguel de Tucuman, T4000 Tucuman, Argentina.
²⁶ Central Laboratory, Del Niño Jesus Hospital, San Miguel de Tucuman, T4000 Tucuman, Argentina.
²⁷ Cochin University Hospital, Biological Immunology Unit, AP-HP, 75014 Paris, France.
²⁸ Inserm/CNRS U944/7212, Paris Cité University, 75006 Paris, France; Hematology Laboratory, Saint-Louis Hospital, AP-HP, 75010 Paris, France; National Reference Center for Bone Marrow Failures, Saint-Louis and Robert Debré Hospitals, 75010 Paris, France.
²⁹ Rare Disease Genomic Medicine Department, Paris Cité University, Necker Hospital for Sick Children, 75015 Paris, France.
³⁰ Department of Virology, Paris Cité University, Cochin Hospital, 75014 Paris, France.
³¹ Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
³² Laboratory of Human Genetics of Infectious Diseases, Inserm U1163, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique Hôpitaux de Paris (AP-HP), 75015 Paris, France.
³³ Immunology Laboratory, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
³⁴ Innate Immunity Unit, Institut Pasteur, 75015 Paris, France; Inserm U1223, 75015 Paris, France; Paris Cité University, 75006 Paris, France.
³⁵ Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes, Lille University, Lille Pasteur Institute, Lille University Hospital, 59000 Lille, France; Neglected Human Genetics Laboratory, Paris Cité University, 75006 Paris, France.
³⁶ Pathology Department, Ambroise-Paré Hospital, AP-HP, 92100 Boulogne-Billancourt, France.
³⁷ Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 0G1, Canada; McGill University Research Centre on Complex Traits, McGill University, Montreal, QC H3A 0G1, Canada; FOCiS Centre of Excellence in Translational Immunology, McGill University, Montreal, QC H3A 0G1, Canada; Department of Physiology, McGill University, Montreal, QC H3A 0G1, Canada.
³⁸ St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584CX Utrecht, the Netherlands.
³⁹ Department of Immunology, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁴⁰ Institute of Experimental Hematology, REBIRTH Center for Regenerative and Translational Medicine, Hannover Medical School, 30625 Hannover, Germany; Department of Pediatric Pulmonology, Allergology and Neonatology and Biomedical Research in Endstage and Obstructive Lung Disease, German Center for Lung Research, Hannover Medical School, 30625 Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, 30625 Hannover, Germany.
⁴¹ Dahdaleh Institute of Genomic Medicine, McGill University, Montreal, QC H3A 0G1, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 0G1, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada.
⁴² Laboratory of Human Genetics of Infectious Diseases, Inserm U1163, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA; Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address: casanova@rockefeller.edu.
⁴³ Dahdaleh Institute of Genomic Medicine, McGill University, Montreal, QC H3A 0G1, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 0G1, Canada.
⁴⁴ Laboratory of Human Genetics of Infectious Diseases, Inserm U1163, 75015 Paris, France; Paris Cité University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA; Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France. Electronic address: jacinta.bustamante@inserm.fr.

Abstract

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.

Keywords: IRF1; Mycobacterium; inborn errors of immunity; interferon-stimulated gene; interferon-γ; macrophages; viruses.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

COVID-19*
Child
Humans
Interferon Regulatory Factor-1
Interferon-alpha
Interferon-gamma
Mycobacterium*
SARS-CoV-2

Substances

Interferon-gamma
Interferon-alpha
IRF1 protein, human
Interferon Regulatory Factor-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding