IFN?-independent control of Mycobacterium tuberculosis infection in rhesus macaques

Control of Mycobacterium tuberculosis (Mtb) infection requires IFN? in mice. In humans, IFN? is critical for resistance to non-tuberculous mycobacteria (NTM), but its role in classic pulmonary tuberculosis is less clear. Here we block IFN?R1 signaling in rhesus macaques at different times post-infection. Short-term IFN? blockade after tuberculoma formation rapidly reduced 18FDG-PET/CT scores of lung inflammation and changed macrophage gene expression. It also increased IFNß, pDCs, plasma cells, killers and IFN-driven gene expression in neutrophils. Blockade started on the day of infection altered T and B cell responses and reduced cytokine levels in granulomas. Surprisingly, IFN? blockade did not affect bacterial loads. We also find that patients with anti-IFN? neutralizing autoantibodies develop extrapulmonary NTM disease, not pulmonary tuberculosis, despite immunological evidence of Mtb exposure. Thus, IFN? has broad immunomodulatory effects during tuberculosis, especially on antiviral-like responses, but control of pulmonary Mtb infection does not require generating high levels of IFN?. Overall design: male rhesus macaques, 3 years old, infecetd with ~40 CFU of Mycobacterium tuberculosis H37Rv