Human IRF1 governs macrophagic IFN-? immunity to mycobacteria

Inborn errors of human IFN-?-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-a/ß-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-a/ß immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-? are, both quantitatively and qualitatively, much stronger than those to IFN-a/ß. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-?. By contrast, IFN-a/ß-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-?-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-a/ß-dependent antiviral immunity. Overall design: Total RNA profiles from primary fibroblasts of the two IRF1 patients, a previously validated IFNGR1 patient, a previously validated IFNGR2 patient, a previously validated IFNAR1 patient, a previously validated IRF9 patient, a previously validated STAT1 patient and three healthy controls. Total RNA profiles from iPSC-derived macrophages of one IRF1 patient, a previously validated IFNGR1 patient, a previously validated STAT1 patient and two healthy controls. Total RNA profiles from monocyte-derived macrophages of one IRF1 patient, a brother of the IRF1 patient, and three healthy controls.