Inflammasomes primarily restrict cytosolicSalmonellareplication within human macrophages

Abstract

AbstractSalmonella entericaserovar Typhimurium is a facultative intracellular pathogen that utilizes its type III secretion systems (T3SSs) to inject virulence factors into the host cell 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 toSalmonellainfection that ultimately restricts intracellular bacterial replication. However, how inflammasomes restrictSalmonellareplication remains unknown. We find that caspase-1 is essential for mediating inflammasome responses toSalmonellaand subsequent restriction of 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 controllingSalmonellareplication in human macrophages. Notably, in the absence of inflammasome responses, we observed hyperreplication ofSalmonellawithin the cytosol of infected cells, and we also observed increased bacterial replication within vacuoles, suggesting that inflammasomes controlSalmonellareplication 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 intracellularSalmonellareplication within human macrophages.