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Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages

Susan L Fink1, Brad T Cookson

  • 1Molecular and Cellular Biology Program, University of Washington, Seattle, WA, USA.

Cellular Microbiology
|July 11, 2006
PubMed

Insights

Salmonella Typhimurium infection triggers pyroptosis, a programmed cell death in macrophages. This process involves caspase-1 activation, leading to membrane pore formation and inflammatory cytokine release.

Area of Science:

  • Microbiology
  • Immunology
  • Cell Biology

Background:

  • Salmonella enterica serovar Typhimurium invades host macrophages.
  • This invasion triggers a unique caspase-1-dependent cell death pathway known as pyroptosis.
  • Pyroptosis is activated during in vivo bacterial infection.

Purpose of the Study:

  • To investigate the mechanisms of pyroptosis induced by Salmonella Typhimurium.
  • To elucidate the role of caspase-1, DNA fragmentation, and the bacterial type III secretion system (TTSS) in this process.
  • To characterize the pore formation and cytokine release during Salmonella-induced pyroptosis.

Main Methods:

  • Analysis of DNA cleavage during pyroptosis.
  • Investigation of poly(ADP-ribose) polymerase (PARP) activity and ATP depletion.
  • Characterization of membrane pore formation using size exclusion.
  • Assessment of requirements for actin cytoskeleton rearrangements, caspase-1, and TTSS.
  • Measurement of inflammatory cytokine release.

Main Results:

  • DNA cleavage during pyroptosis is mediated by caspase-1-stimulated nuclease activity.
  • Rapid lysis of Salmonella-infected macrophages does not depend on PARP activity or DNA fragmentation.
  • Membrane pores (1.1–2.4 nm) form during pyroptosis, causing cell swelling and osmotic lysis.
  • Pore formation requires host actin rearrangements, caspase-1, and the bacterial TTSS, but TTSS translocon insertion alone is insufficient.
  • Inflammatory cytokines are released concurrently with pore formation.

Conclusions:

  • Pyroptosis is a caspase-1-mediated inflammatory programmed cell death pathway.
  • The mechanism involves TTSS-dependent pore formation, leading to cell lysis and cytokine release.
  • This study provides further evidence for pyroptosis as a critical host defense mechanism against Salmonella infection.

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