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bioRxiv · 10.1101/238873

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

Bhattacharya, B.·Chatterjee, S.·Berland, R.·Pichugin, A.·Ivanov, A.·Connor, J. H.·Yan, B.-S.·Kobzik, L.·Kramnik, I.
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Abstract

Host susceptibility to tuberculosis and several other intracellular bacteria is controlled by a mouse genetic locus, sst1. Necrotic inflammatory lesions, similar to human TB granulomas, are a hallmark of the sst1 susceptible phenotype. Our previous work established that increased disease severity in sst1 susceptible mice reflects dysfunctional macrophage effector or tolerance mechanisms, but the molecular mechanisms have been unclear.\n\nWe demonstrate that sst1-deficient macrophages develop aberrant, biphasic responses to TNF, characterized by super-induction of stress and type I interferon pathways after prolonged TNF stimulation. This late stage response was initiated by oxidative stress and Myc. It was driven via a JNK - IFN{beta} - PKR feed-forward circuit locking the susceptible macrophages in a state of escalating stress. Consequently, prolonged TNF stimulation of the susceptible macrophages reduced their resilience to subsequent infection with intracellular bacteria.\n\nThe data support a generalizable paradigm in host - pathogen interactions, where susceptibility emerges gradually within inflammatory tissue due to imbalanced macrophage responses to growth, differentiation, activation 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.

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Bhattacharya, B., Chatterjee, S., Berland, R., Pichugin, A., Ivanov, A., Connor, J. H., Yan, B.-S., Kobzik, L., Kramnik, I.. 2017-12-22. Macrophage resilience and control of intracellular bacteria requires sst1-dependent integration of c-Myc, stress response and type I IFN pathways. https://doi.org/10.1101/238873

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