Integrated Stress Responses to Bacterial Pathogenesis Patterns

Abstract

Activation of an appropriate innate immune response to bacterial infection is critical to limit microbial spread and generate cytokines and chemokines to instruct appropriate adaptive immune responses. Recognition of bacteria or bacterial products by pattern recognition molecules is crucial to initiate this response. However, it is increasingly clear that the context in which this recognition occurs can dictate the quality of the response and determine the outcome of an infection. The cross talk established between host and pathogen results in profound alterations on cellular homeostasis triggering specific cellular stress responses. In particular, the highly conserved integrated stress response (ISR) has been shown to shape the host response to bacterial pathogens by sensing cellular insults resulting from infection and modulating transcription of key genes, translation of new proteins and cell autonomous antimicrobial mechanisms such as autophagy. Here, we review the growing body of evidence demonstrating a role for the ISR as an integral part of the innate immune response to bacterial pathogens.

Mitochondrial stress-dependent regulation of cellular protein synthesis

“…Indeed, multiple endogenous and exogenous stressors influence protein synthesis by initiating signaling cascades that lead to the attenuation of translation ( Fig. 1; García et al, 2007;Grant, 2011;Harding et al, 1999Harding et al, , 2003Liu et al, 2008;Rodrigues et al, 2018). Activation of the integrated stress response (ISR; Bernales et al, 2006;Harding et al, 2000) or inhibition of mechanistic/mammalian target of rapamycin (mTOR; Ben-Sahra and Manning, 2017;Hay and Sonenberg, 2004;Shimobayashi and Hall, 2014;Yoon, 2017) are well-established stress response pathways.…”

Guardians of the Cell: Effector-Triggered Immunity Steers Mammalian Immune Defense

“…Other changes in the cell sensed by innate receptors are membrane damage; for example, some enteroinvasive bacteria can induce depletion of amino acids by membrane damage, resulting in the activation of mammalian target of rapamycin (mTOR)-controlled autophagy or the integrated stress response via the general control non-de-repressible 2 kinase (GCN2, EIF2AK4), as demonstrated in Shigella-infected human cell lines [52]. Many bacteria, including Brucella abortus and Chlamydia muridarum, are known to induce endoplasmic reticulum (ER) stress responses, resulting in activation of the unfolded protein response (UPR) effectors, inositol-requiring enzyme (IRE)1α, ATF6, and PRKR-like endoplasmic reticulum kinase (PERK) (Figure 1) [53]. Upon mouse infection with Brucella and Chlamydia, UPR can ultimately lead to the activation of inflammatory pathways by an IREα-mediated TRAF2-NOD1/2 pathway that is independent of NOD1/2-mediated peptidoglycan sensing [54].…”

The eIF2α kinase HRI in innate immunity, proteostasis, and mitochondrial stress

“…Indeed, Salmonella, Shigella, and Listeria infection were shown to induce eIF2a phosphorylation [24][25][26] thereby demonstrating that ISR activation occurs as a result of patterns of bacterial pathogenesis such as bacterial growth, membrane damage, access to cytosol, and cytoskeleton disruption (see for review Ref. [27]). Moreover, Shresta et al have reported that cells lacking HRI are highly resistant to infection by bacterial pathogens, including Yersinia, Chlamydia, and Listeria [28].…”