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Macrophage activation redirects yersinia-infected host cell death from apoptosis to caspase-1-dependent pyroptosis

Tessa Bergsbaken1, Brad T Cookson

  • 1Department of Microbiology, University of Washington, Seattle, Washington, United States of America.

Plos Pathogens
|November 7, 2007
PubMed

Insights

Yersinia infection shifts macrophage death from apoptosis to pyroptosis. Host cell activation, triggered by Toll-like receptor (TLR) ligands, redirects cell death mechanisms, impacting inflammatory responses.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • Yersinia species induce YopJ-dependent apoptosis in naive macrophages.
  • Macrophages activated with lipopolysaccharide (LPS) resist YopJ-dependent apoptosis but become susceptible to other Yersinia virulence factors.

Purpose of the Study:

  • To investigate the mechanism of Yersinia-induced macrophage death in activated versus naive cells.
  • To determine the role of caspase-1 activation and pyroptosis in Yersinia infection.

Main Methods:

  • Infection of macrophages with Yersinia species (Yptb, Y. pestis) under various activation states (LPS, TLR ligands, nonviable bacteria).
  • Analysis of cell death pathways, including apoptosis and pyroptosis, by assessing caspase activation (caspase-1, caspase-3), membrane permeability, DNA damage, and IL-18 release.
  • In vivo studies of Yptb infection in mice.

Main Results:

  • Activated macrophages, resistant to YopJ-dependent apoptosis, undergo caspase-1-dependent pyroptosis upon Yersinia infection.
  • Yersinia pseudotuberculosis lacking YopJ induces pyroptosis in activated macrophages, dependent on the type III translocon but not translocated effectors.
  • Wild-type Yersinia infection in activated macrophages also results in pyroptosis, with delayed caspase-3 activation.
  • Macrophage activation via various TLR ligands or nonviable bacteria induces susceptibility to pyroptosis.

Conclusions:

  • Host cell activation during Yersinia infection fundamentally alters macrophage death pathways.
  • The transition from non-inflammatory apoptosis to inflammatory pyroptosis is mediated by host signaling, not solely bacterial factors.
  • This switch has significant implications for the inflammatory consequences of Yersinia infection.

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