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 infection that ultimately restricts intracellular bacterial replication. However, how inflammasomes restrict replication remains unknown. We find that caspase-1 is essential for mediating inflammasome responses to 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 replication in human macrophages. Notably, in the absence of inflammasome responses, we observed hyperreplication of within the cytosol of infected cells as well as increased bacterial replication within vacuoles, suggesting that inflammasomes control 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 replication within human macrophages.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370064PMC
http://dx.doi.org/10.1101/2023.07.17.549348DOI Listing

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