Human IRF1 governs phagocytic IFN-? immunity to mycobacteria but not cell-intrinsic IFN-a/b immunity to viruses [scRNAseq]

Inborn errors of human IFN-? immunity underlie mycobacterial diseases, while inborn errors of IFN-a/b 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. They have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2 that is life-threatening in individuals with deficient IFN-a/b. There is a much greater IRF1-dependent response to IFN-? than IFN-a/b in vitro, both quantitatively and qualitatively. Monocyte-derived macrophages and iPSC-derived macrophages of both patients do not upregulate at least 40% of target genes normally induced by IFN-?. In contrast, cell-intrinsic IFN-a/b immunity to a wide range of viruses, including HIV and SARS-CoV-2, is maintained. Human IRF1 is thus largely redundant for antiviral IFN-a/b immunity across cell types. By contrast, human IRF1 is essential for IFN-? immunity to mycobacteria in mononuclear myeloid cells. Overall design: To investigate the impact of IRF1 loss-of-function on the development of immune cells and their transcriptional program, we have performed scRNA-seq on PBMC from 1 pediatric IRF1 deficient patient (P1.1). This dataset has been combined with CITE-seq for a second sample obtained for this patient (P1.2) and a second IRF1 deficient patient (P2), together with healthy controls. To investigate the impact of IRF1 loss-of-function on the development of immune cells and their transcriptional program, we have performed scRNA-seq on PBMC from 1 pediatric IRF1 deficient patient. This dataset has been combined with CITE-seq for a second sample obtained for this patient and a second IRF1 deficient patient, together with healthy controls.