| Autor: |
Egan MS; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., O'Rourke EA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Mageswaran SK; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Zuo B; Electron Microscopy Resource Laboratory, Department of Biochemistry & Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Martynyuk I; Electron Microscopy Resource Laboratory, Department of Biochemistry & Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Demissie T; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Hunter EN; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Bass AR; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Chang YW; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Brodsky IE; Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA., Shin S; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. |
| Abstrakt: |
Salmonella enterica 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 Salmonella infection that ultimately restricts intracellular bacterial replication. However, how inflammasomes restrict Salmonella replication remains unknown. We find that caspase-1 is essential for mediating inflammasome responses to Salmonella 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 Salmonella replication in human macrophages. Notably, in the absence of inflammasome responses, we observed hyperreplication of Salmonella within the cytosol of infected cells as well as increased bacterial replication within vacuoles, suggesting that inflammasomes control Salmonella 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 Salmonella replication within human macrophages. |
