Salmonella pathogenicity island 2-dependent macrophage death is mediated in part by the host cysteine protease caspase-1

Cell Microbiol. 2001 Dec;3(12):825-37. doi: 10.1046/j.1462-5822.2001.00162.x.


Salmonella typhimurium invades host macrophages and can either induce a rapid cell death or establish an intracellular niche within the phagocytic vacuole. Rapid cell death requires the Salmonella pathogenicity island (SPI)1 and the host protein caspase-1, a member of the pro-apoptotic caspase family of proteases. Salmonella that do not cause this rapid cell death and instead reside in the phagocytic vacuole can trigger macrophage death at a later time point. We show here that the human pathogen Salmonella typhi also triggers both rapid, caspase-1-dependent and delayed cell death in human monocytes. The delayed cell death has previously been shown with S. typhimurium to be dependent on SPI2-encoded genes and ompR. Using caspase-1(-/-) bone marrow-derived macrophages and isogenic S. typhimurium mutant strains, we show that a large portion of the delayed, SPI2-dependent death is mediated by caspase-1. The two known substrates of activated caspase-1 are the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and IL-18, which are cleaved to produce bioactive cytokines. We show here that IL-1beta is released during both SPI1- and SPI2-dependent macrophage killing. Using IL-1beta(-/-) bone marrow-derived macrophages and a neutralizing anti-IL-18 antibody, we show that neither IL-1beta nor IL-18 is required for rapid or delayed macrophage death. Thus, both rapid, SPI1-mediated killing and delayed, SPI2-mediated killing require caspase-1 and result in the secretion of IL-1beta, which promotes inflammation and may facilitate the spread of Salmonella beyond the gastrointestinal tract in systemic disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Bacterial Proteins / metabolism*
  • Caspase 1 / genetics
  • Caspase 1 / metabolism*
  • Cell Line
  • Enzyme Activation
  • Humans
  • Interleukin-1 / biosynthesis
  • Interleukin-1 / metabolism
  • Interleukin-18 / metabolism
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / microbiology*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Salmonella typhi / metabolism
  • Salmonella typhi / pathogenicity*
  • Salmonella typhimurium / metabolism
  • Salmonella typhimurium / pathogenicity*
  • Time Factors
  • U937 Cells


  • Bacterial Proteins
  • Interleukin-1
  • Interleukin-18
  • Membrane Proteins
  • SPI-2 protein, Salmonella
  • Spi1 protein, Salmonella
  • Caspase 1