Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death.
Sensing bacterial products in the cytosol of mammalian cells by NOD-like receptors leads to the activation of caspase-1 inflammasomes, and the production of the pro-inflammatory cytokines interleukin (IL)-18 and IL-1β. In addition, mouse caspase-11 (represented in humans by its orthologs, caspase-4 and caspase-5) detects cytosolic bacterial LPS directly. Activation of caspase-1 and caspase-11 initiates pyroptotic host cell death that releases potentially harmful bacteria from the nutrient-rich host cell cytosol into the extracellular environment. Here we use single cell analysis and time-lapse microscopy to identify a subpopulation of host cells, in which growth of cytosolic Salmonella Typhimurium is inhibited independently or prior to the onset of cell death. The enzymatic activities of caspase-1 and caspase-11 are required for growth inhibition in different cell types. Our results reveal that these proteases have important functions beyond the direct induction of pyroptosis and proinflammatory cytokine secretion in the control of growth and elimination of cytosolic bacteria.
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Flowers Building Exhibition Road, London SW7 2AZ, UK.
Teresa L M
TL
Thurston
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Flowers Building Exhibition Road, London SW7 2AZ, UK.
Sophie A
SA
Matthews
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Flowers Building Exhibition Road, London SW7 2AZ, UK.
Elliott
E
Jennings
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Flowers Building Exhibition Road, London SW7 2AZ, UK.
Eric
E
Alix
National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China.
Feng
F
Shao
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Flowers Building Exhibition Road, London SW7 2AZ, UK.
Avinash R
AR
Shenoy
Respiratory Pharmacology, Pharmacology &Toxicology Section, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK.
Mark A
MA
Birrell
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Flowers Building Exhibition Road, London SW7 2AZ, UK.
David W
DW
Holden
D016475:3T3 Cells; D000818:Animals; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053471:Caspases, Initiator; D003600:Cytosol / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000382:microbiology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000069292:Pyroptosis / Q000276:immunology*; D012480:Salmonella Infections / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000187:drug effects / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D059010:Single-Cell Analysis; D059008:Time-Lapse Imaging
D058847:Inflammasomes; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; C000628184:Casp1 protein, mouse; D020170:Caspase 1