Listeria monocytogenes induces an interferon‐enhanced activation of the integrated stress response that is detrimental for resolution of infection in mice

Abstract

Type I interferons (IFNs) induce a detrimental response during Listeria monocytogenes (L. monocytogenes) infection. We were interested in identifying mechanisms linking IFN signaling to negative host responses against L. monocytogenes infection. Herein, we found that infection of myeloid cells with L. monocytogenes led to a coordinated induction of type I IFNs and activation of the integrated stress response (ISR). Infected cells did not induce Xbp1 splicing or BiP upregulation, indicating that the unfolded protein response was not triggered. CHOP (Ddit3) gene expression was upregulated during the ISR activation induced by L. monocytogenes. Myeloid cells deficient in either type I IFN signaling or PKR activation had less upregulation of CHOP following infection. CHOP‐deficient mice showed lower expression of innate immune cytokines and were more resistant than wild‐type counterparts following L. monocytogenes infection. These findings indicate that L. monocytogenes infection induces type I IFNs, which activate the ISR through PKR, which contributes to a detrimental outcome in the infected host.

The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas

“…This escalating stress proceeds via super-induction of IFNb, activation of the IFNb-PKR-ISR axis and subsequent upregulation of pro-apoptotic genes and proteins. This mechanism is similar to a signaling cascade recently described in a model of Listeria monocytogenes infection (49).…”

Increased susceptibility to intracellular bacteria and necrotic inflammation driven by a dysregulated macrophage response to TNF

“…The unusual, second wave of ISR activation is exclusive for the sst1-susceptible phenotype. It is initiated by TNF in IFN-I-dependent manner via PKR activation, similar to a cascade recently described in a model of Listeria monocytogenes infection [54]. However, in the sst1-susceptible macrophages, the IFNb super-induction was triggered by TNF alone.…”

“…For example, upregulation of JNK by proteotoxic stress induced by TNF may lead to transient activation of the IFNb -PKR -ISR axis to limit global protein biosynthesis by inhibiting cap-dependent translation. However, un-resolving proteotoxic stress and persistent ISR observed in susceptible macrophages lead to further escalation of JNK activity, corresponding increase in IFNb production and upregulation of interferon-stimulated genes PKR, Rsad2 and Ch25h, whose products inhibit protein biosynthesis, mitochondrial function and lipogenesis, respectively [54,60,61]. The 25hydrocholesterol produced by the Ch25h enzymatic activity can further increase ISR [62] and amplify inflammatory cytokine production [63].…”

The integrated stress response mediates type I interferon driven necrosis in Mycobacterium tuberculosis granulomas

“…Our studies reveal a mechanism of stress-mediated IFN-I pathway upregulation that makes macrophages less resilient to subsequent infection with intracellular bacteria and is associated with immunopathology in vivo. We propose that stress- Rsad2 and Ch25h, whose products inhibit protein biosynthesis, mitochondrial function and lipogenesis, respectively 56,72,73 . The 25-hydrocholesterol produced by the Ch25h enzymatic activity can further increase the ISR 74 and amplify inflammatory cytokine production 75 .…”