The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas
Bidisha Bhattacharya, … , William Bishai, Igor Kramnik
Bidisha Bhattacharya, … , William Bishai, Igor Kramnik
Published December 10, 2020
Citation Information: J Clin Invest. 2021;131(3):e130319. https://doi.org/10.1172/JCI130319.
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Research Article Immunology Infectious disease

The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas

Abstract

The mechanism by which only some individuals infected with Mycobacterium tuberculosis develop necrotic granulomas with progressive disease while others form controlled granulomas that contain the infection remains poorly defined. Mice carrying the sst1-suscepible (sst1S) genotype develop necrotic inflammatory lung lesions, similar to human tuberculosis (TB) granulomas, which are linked to macrophage dysfunction, while their congenic counterpart (B6) mice do not. In this study we report that (a) sst1S macrophages developed aberrant, biphasic responses to TNF characterized by superinduction of stress and type I interferon pathways after prolonged TNF stimulation; (b) the late-stage TNF response was driven via a JNK/IFN-β/protein kinase R (PKR) circuit; and (c) induced the integrated stress response (ISR) via PKR-mediated eIF2α phosphorylation and the subsequent hyperinduction of ATF3 and ISR-target genes Chac1, Trib3, and 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. Hence, induction of the ISR and the locked-in state of escalating stress driven by the type I IFN pathway in sst1S macrophages play a causal role in the development of necrosis in TB granulomas. Interruption of the aberrant stress response with inhibitors such as ISRIB may offer novel host-directed therapy strategies.

Authors

Bidisha Bhattacharya, Shiqi Xiao, Sujoy Chatterjee, Michael Urbanowski, Alvaro Ordonez, Elizabeth A. Ihms, Garima Agrahari, Shichun Lun, Robert Berland, Alexander Pichugin, Yuanwei Gao, John Connor, Alexander R. Ivanov, Bo-Shiun Yan, Lester Kobzik, Bang-Bon Koo, Sanjay Jain, William Bishai, Igor Kramnik

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Figure 4

Global quantitative assessment of the ISRIB effect on pulmonary TB lesions using ex vivo MRI imaging.

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Global quantitative assessment of the ISRIB effect on pulmonary TB lesio...
The B6.Sst1S mice were infected with M. tuberculosis by aerosol. The ISRIB was administered i.p. for 4 weeks starting at 4 weeks after infection. (A) Representative MRI sections of lungs at lower, middle, and upper levels of B6.Sst1S mice (M1–M6) at 8 weeks after infection (3 animals per group). Left panels = control mice; right panels = mice treated with ISRIB (1 mg/kg) for 4 weeks. (B) Distribution of size and intensity of individual lesions, as denoted by horizontal and vertical lines, respectively. Lung lesions of control (gray lines) and ISRIB-treated (red lines) B6.Sst1S mice treated for 24 (left panel) and 4 weeks (right panel) with ISRIB (1 mg/kg). (C) statistical analysis demonstrating the effect of the 4-week ISRIB treatment on the lesion intensity stratified by the lesion size.