Human IRF1 governs phagocytic IFN-gamma immunity to mycobacteria

Inborn errors of human IFN-? immunity underlie mycobacterial diseases, whereas inborn errors of IFN-?/? immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe two unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria. 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-?/? immunity. The IRF1-dependent cellular responses to IFN-? are, both quantitatively and qualitatively, much greater than those to IFN-?/? in vitro. Monocyte- and iPSC-derived macrophages from the two patients show no upregulation of at least 20% of the target genes normally induced by IFN-?. By contrast, cell-intrinsic IFN-?/? immunity to diverse viruses, including SARS-CoV-2, is intact. Human IRF1 is, thus, largely redundant for antiviral IFN-?/? immunity. By contrast, human IRF1 is essential for IFN-? immunity to mycobacteria in myeloid cells. Overall design: Primary fibroblasts, M-CSF-iPSC-derived macrophages, and M-CSF-IL-4-monocytes-derived macrophages were stimulated or not 30 minutes, 2 hours, or 8 hours with 1000 IU/mL of IFN-alpha or IFN-gamma