Coupling ER stress to STAT1-mediated immunity against bacterial infection
Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are hallmarks of pathogen infection. The UPR drives pro-inflammatory responses to ER stress but its role in interferon signaling is unknown. Using metabolomics approaches, we observed that pharmacological ER stress reprogrammed macrophage metabolism to a pro-inflammatory “M1-like” phenotype and enhanced the microbicidal activity of these cells to restrict bacterial infection. Phospho-proteomics analysis showed that this anti-microbial response was mediated via the UPR serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1) and activation of signal transducer and transcription activator 1 (STAT1) required for interferon signaling. We also demonstrated that blockade of IRE1 signaling by the bacterial pathogen Legionella pneumophila inhibited STAT1-mediated immune responses to infection. These findings reveal the potential for ER stress to initiate anti-microbial STAT1 signaling in the absence of other pro-inflammatory stimuli and how this response is inhibited by a bacterial pathogen during infection. Overall design: To investigate the role of Legionella effector proteins on host mRNA expression, THP-1 macrophages were infected with the Legionella pneumophila 130b strain (WT) or a mutant strain lacking four genes encoding Lgt1-3, SidI and SidL (delta4). We then performed comparitive gene expression profiling of RNA-seq data from WT versus delta4 infected cells from three independent experiments.