Diverse roles of endoplasmic reticulum stress sensors in bacterial infection

Abstract

Bacterial infection often leads to cellular damage, primarily marked by loss of cellular integrity and cell death. However, in recent years, it is being increasingly recognized that, in individual cells, there are graded responses collectively termed cell-autonomous defense mechanisms that induce cellular processes designed to limit cell damage, enable repair, and eliminate bacteria. Many of these responses are triggered not by detection of a particular bacterial effector or ligand but rather by their effects on key cellular processes and changes in homeostasis induced by microbial effectors when recognized. These in turn lead to a decrease in essential cellular functions such as protein translation or mitochondrial respiration and the induction of innate immune responses that may be specific to the cellular deficit induced. These processes are often associated with specific cell compartments, e.g., the endoplasmic reticulum (ER). Under non-infection conditions, these systems are generally involved in sensing cellular stress and in inducing and orchestrating the subsequent cellular response. Thus, perturbations of ER homeostasis result in accumulation of unfolded proteins which are detected by ER stress sensors in order to restore the normal condition. The ER is also important during bacterial infection, and bacterial effectors that activate the ER stress sensors have been discovered. Increasing evidence now indicate that bacteria have evolved strategies to differentially activate different arms of ER stress sensors resulting in specific host cell response. In this review, we will describe the mechanisms used by bacteria to activate the ER stress sensors and discuss their role during infection.

LACC1 Required for NOD2-Induced, ER Stress-Mediated Innate Immune Outcomes in Human Macrophages and LACC1 Risk Variants Modulate These Outcomes

“…The role of ER stress in microbial clearance has been mostly examined in epithelial cells or mouse myeloid cells, with mechanisms mediating this clearance still incompletely defined. Previous studies found that different branches of ER stress can either enhance or inhibit microbial growth depending on the microbe, infection conditions, or the host species (Pillich et al, 2016). We find that in NOD2-stimulated human MDMs, ER stress leads to enhanced bacterial clearance.…”

Toll‐like receptor 2 (TLR2) engages endoplasmic reticulum stress sensor IRE1α to regulate retinal innate responses in Staphylococcus aureus endophthalmitis

“…27 Both TLRsignaling and IRE1-mediated splicing of Xbp1 have been shown to invoke innate immune responses and the production of inflammatory cytokines. 27,36,45,60 Our data demonstrated that inhibiting IRE1α attenuates S aureus-induced cytokine production in vivo (mouse model of endophthalmitis) as well as in cultured microglia, implicating its role in regulating the inflammatory innate immune response. The experiments using BMDM from myeloid cell-specific IRE1 −/− mice further validates these findings by showing inhibition of S aureus-induced inflammatory mediators.…”

“…Bacterial infections have been shown to trigger an UPR 35,36 resulting in the activation of the ER-transmembrane protein IRE1α. Although multiple targets for the IRE1α endonuclease have been identified, the splicing of Xbp1 mRNA is the main under infectious and inflammatory conditions.…”

Molecular biology of the gut

“…The workshop has also discussed the more global defects at the cellular levels such as in celiac disease, microvillus inclusion disease, or cystic fibrosis which also elicit chronic diarrhea [ 7 – 9 ]. Altogether, these disorders lead to substantial alterations of the intestinal microbiota and may alter and disturb the finely tuned intestinal hemostasis [ 10 ]. In fact, the gut mucosa is continuously exposed to bacterial and dietary antigens found in the lumen and microbial infections can stress and regulate the epithelial cell integrity and physiology.…”