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 (sst1^S) 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) sst1^S 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 sst1^S 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 sst1^S 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.

Patients treated with dialysis have high rates of brain infarcts, brain atrophy, and white matter disease. There are limited data regarding the presence of more subtle damage to brain white matter. In the Cognition and Dialysis Study, we compared brain structure using diffusion tensor imaging in hemodialysis (HD) patients to individuals without known kidney disease, using tract based spatial statistics (TBSS) to compare Fractional Anisotropy (FA) and Mean Diffusivity (MD). Statistical comparison of each overlaid voxel was age controlled using a permutation based corrected p value of <0.05. Thirty-four HD patients and twenty six controls (52 vs 51 years for HD vs control) had adequate magnetic resonance imaging for analysis. The HD group had fewer women (38% vs 23%) and a higher prevalence of diabetes (29% vs 8%), heart failure (29% vs 0%) and clinical stroke (15% vs 0%). Hemodialysis patients had significantly lower FA across multiple white matter fiber tracts, with fronto-temporal connections, the genu of the corpus callosum and the fornix more significantly affected than posterior regions of the brain. Similarly, HD patients had significantly higher mean diffusivity in multiple anterior brain regions. Results remained similar when those with a prior history of stroke were excluded. In HD patients, there is more white matter disease in the anterior than posterior parts of the brain compared to controls without kidney disease. This pattern of injury is most similar to that seen in aging, suggesting that developing chronic kidney disease and ultimately kidney failure may result in a phenotype consistent with accelerated aging.