Macrophage resilience and control of intracellular bacteria requires sst1-dependent integration of c-Myc, stress response and type I IFN pathways

The development of protective immunity vs immunopathology in tuberculosis is controlled by a mouse genetic locus, sst1, which mediates formation of human-like necrotic granulomas, but its molecular mechanisms have been unclear. We demonstrate that sst1 deficient macrophages develop aberrant, biphasic responses to TNF, characterized by super-induction of IFNb and ISR pathways after prolonged TNF stimulation. This late stage was initiated by oxidative stress and driven by Myc via a JNK - IFNb - PKR feed forward circuit. By locking the susceptible macrophages in a state of escalating stress, prolonged TNF stimulation reduces resilience to subsequent infection with intracellular bacteria. We propose a generalizable paradigm in host - pathogen interactions, where susceptibility emerges gradually within inflammatory tissue due to imbalanced macrophage responses to growth, differentiation and stress stimuli prior to encountering pathogens. This explains how successful pathogens may locally bypass mechanisms of resistance in otherwise immunocompetent hosts and suggests novel therapeutic strategies.