Translation inhibition by bacterial pathogens: links to inflammation (INM1P.428)

Abstract

Abstract Legionella pneumophila is an intracellular bacterial pathogen that is the cause of a severe pneumonia in humans called Legionnaires’ Disease. L. pneumophila infects alveolar macrophages and its virulence requires a type IV secretion system (T4SS) that injects bacterial effector proteins into the host cytosol. Macrophages distinguish infection with T4SS+ (virulent) and T4SS- (avirulent) bacteria, and mount several distinct immune responses to virulent bacteria. Virulent L. pneumophila induces a block in host protein synthesis that is partially induced by 7 bacterial effectors that directly block host translation. L. pneumophila infection also induces the inflammatory cytokine IL-1α. We link translation inhibition to the production of IL-1α, and show that IL-1α signaling, through the interleukin-1 receptor, protects the host during L. pneumophila infection. We show that translation inhibition leads to a sustained production of Il1a transcript and we suggest that this overcomes the block in translation and allows for preferential production of inflammatory cytokines in infected macrophages. To gain insight into the L. pneumophila induced block in host translation, we used ribosome profiling and RNAseq of L. pneumophila infected macrophages to analyze global and mRNA-specific translation rates. Our data suggest that translation inhibition induced by pathogenic infection may be an important pathway that induces inflammation and protects animals from multiple bacterial pathogens.