RT Journal Article SR Electronic T1 The integrated stress response mediates type I interferon driven necrosis in Mycobacterium tuberculosis granulomas JF bioRxiv FD Cold Spring Harbor Laboratory SP 499467 DO 10.1101/499467 A1 Bidisha Bhattacharya A1 Shiqi Xiao A1 Sujoy Chatterjee A1 Michael Urbanowski A1 Alvaro Ordonez A1 Elizabeth A. Ihms A1 Garima Agrahari A1 Shichun Lun A1 Robert Berland A1 Alexander Pichugin A1 Yuanwei Gao A1 John Connor A1 Alexander Ivanov A1 Bo-Shiun Yan A1 Lester Kobzik A1 Sanjay Jain A1 William Bishai A1 Igor Kramnik YR 2018 UL http://biorxiv.org/content/early/2018/12/19/499467.abstract AB Necrosis in the tuberculous granuloma is a hallmark of tuberculosis that enables pathogen survival and transmission. Susceptibility to tuberculosis and several other intracellular bacteria is controlled by a mouse genetic locus, sst1, and mice carrying the sst1-suscepible (sst1S) genotype develop necrotic inflammatory lung lesions, similar to human TB granulomas. Our previous work established that increased disease severity in sst1S mice reflects dysfunctional macrophage effector or tolerance mechanisms, but the molecular mechanisms have remained unclear. Here we demonstrate that sst1S macrophages develop aberrant, biphasic responses to TNF characterized by super-induction of stress and type I interferon pathways after prolonged TNF stimulation with this late-stage response being initiated by oxidative stress and Myc activation and driven via a JNK - IFNβ - PKR circuit. This circuit leads to induction of the integrated stress response (ISR) mediated by eIF2α phosphorylation and the subsequent hyper-induction of ATF3 and ISR-target genes Chac1, Trib3, Ddit4. The administration of ISRIB, a small molecule inhibitor of the ISR, blocked the development of necrosis in lung granulomas of M. tuberculosis-infected sst1S mice and concomitantly reduced the bacterial burden revealing that induction of the ISR and the locked-in state of escalating stress driven by type I IFN pathway in sst1S macrophages plays a causal role in the development of necrosis. Our data support a generalizable paradigm in intracellular pathogen-host interactions wherein host susceptibility emerges within inflammatory tissue due to imbalanced macrophage responses to growth, differentiation, activation and stress stimuli. Successful pathogens such as M. tuberculosis may exploit this aberrant response in susceptible hosts to induce necrotic lesions that favor long-term pathogen survival and transmission. Interruption of the aberrant stress response with inhibitors such as ISRIB may offer novel therapeutic strategies.