Inflammasomes primarily restrict cytosolic <i>Salmonella</i> replication within human macrophages.

Abstract

<i>Salmonella enterica</i> serovar Typhimurium is a facultative intracellular pathogen that utilizes its type III secretion systems (T3SSs) to inject virulence factors into host cells and colonize the host. In turn, a subset of cytosolic immune receptors respond to T3SS ligands by forming multimeric signaling complexes called inflammasomes, which activate caspases that induce interleukin-1 (IL-1) family cytokine release and an inflammatory form of cell death called pyroptosis. Human macrophages mount a multifaceted inflammasome response to <i>Salmonella</i> infection that ultimately restricts intracellular bacterial replication. However, how inflammasomes restrict <i>Salmonella</i> replication remains unknown. We find that caspase-1 is essential for mediating inflammasome responses to <i>Salmonella</i> and restricting bacterial replication within human macrophages, with caspase-4 contributing as well. We also demonstrate that the downstream pore-forming protein gasdermin D (GSDMD) and Ninjurin-1 (NINJ1), a mediator of terminal cell lysis, play a role in controlling <i>Salmonella</i> replication in human macrophages. Notably, in the absence of inflammasome responses, we observed hyperreplication of <i>Salmonella</i> within the cytosol of infected cells as well as increased bacterial replication within vacuoles, suggesting that inflammasomes control <i>Salmonella</i> replication primarily within the cytosol and also within vacuoles. These findings reveal that inflammatory caspases and pyroptotic factors mediate inflammasome responses that restrict the subcellular localization of intracellular <i>Salmonella</i> replication within human macrophages.