Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria.

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/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-α/ß 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/ß. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/ß-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/ß-dependent antiviral immunity.

Microbiome Modulation as a Novel Strategy to Treat and Prevent Respiratory Infections.

Acute and chronic lower airway disease still represent a major cause of morbidity and mortality on a global scale. With the steady rise of multidrug-resistant respiratory pathogens, such as Pseudomonas aeruginosa and Klebsiella pneumoniae, we are rapidly approaching the advent of a post-antibiotic era. In addition, potentially detrimental novel variants of respiratory viruses continuously emerge with the most prominent recent example being severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To this end, alternative preventive and therapeutic intervention strategies will be critical to combat airway infections in the future. Chronic respiratory diseases are associated with alterations in the lung and gut microbiome, which is thought to contribute to disease progression and increased susceptibility to infection with respiratory pathogens. In this review we will focus on how modulating and harnessing the microbiome may pose a novel strategy to prevent and treat pulmonary infections as well as chronic respiratory disease.