Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Creative Commons License

Rosain J., Neehus A., Manry J., Yang R., Le Pen J., Daher W., ...More

Cell, vol.186, no.3, pp.621, 2023 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 186 Issue: 3
  • Publication Date: 2023
  • Doi Number: 10.1016/j.cell.2022.12.038
  • Journal Name: Cell
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database, DIALNET
  • Page Numbers: pp.621
  • Keywords: inborn errors of immunity, interferon-stimulated gene, interferon-γ, IRF1, macrophages, Mycobacterium, viruses
  • Bezmialem Vakıf University Affiliated: Yes

Abstract

© 2022Inborn 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.