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Enteropathogenic Escherichia coli Stimulates Effector-Driven Rapid Caspase-4 Activation in Human Macrophages

Philippa J Goddard1, Julia Sanchez-Garrido2, Sabrina L Slater3

  • 1Department of Life Sciences, Medical Research Council Centre for Molecular Bacteriology & Infection, Imperial College London, London, UK; Department of Medicine, Medical Research Council Centre for Molecular Bacteriology & Infection, Imperial College London, London, UK.

Cell Reports
|April 25, 2019
PubMed

Insights

Enteropathogenic Escherichia coli (EPEC) triggers inflammasome activation in macrophages. This process involves caspase-4 and caspase-1, leading to pyroptosis and cytokine release, crucial for host defense against bacterial infection.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • Microbial infections activate inflammasomes, initiating inflammatory responses via caspase-1.
  • Enteropathogenic Escherichia coli (EPEC) is a gastrointestinal pathogen that manipulates host cell actin polymerization.
  • The type 3 secretion system (T3SS) delivers bacterial effectors, including Tir, essential for EPEC pathogenesis.

Purpose of the Study:

  • To investigate the mechanism by which EPEC activates inflammasomes in human macrophages.
  • To elucidate the roles of caspase-4 and the NLRP3 inflammasome in EPEC infection.
  • To identify the bacterial factors and host cell processes involved in inflammasome activation by EPEC.

Main Methods:

  • Human macrophages were infected with EPEC.
  • inflammasome activation was assessed by measuring caspase-1 and caspase-4 activation and cytokine processing.
  • Tir-intimin signaling and its role in inflammasome activation were studied using wild-type and engineered E. coli strains.

Main Results:

  • EPEC induced rapid, T3SS-dependent non-canonical NLRP3 inflammasome activation in human macrophages.
  • Caspase-4 activation by EPEC was dependent on lipopolysaccharide (LPS) and EPEC-induced actin polymerization, mediated by Tir, NCK, and TccP.
  • EPEC infection triggered pyroptosis and cytokine processing via the NLRP3-caspase-1 inflammasome, initiated by caspase-4.
  • Reconstitution of Tir-intimin signaling in E. coli K12 was sufficient to activate the inflammasome, confirming the critical role of this pathway.

Conclusions:

  • EPEC hijacks the host immune system by activating caspase-4 and the NLRP3 inflammasome, leading to pyroptosis and cytokine release.
  • A novel crosstalk between caspase-4 and caspase-1 is revealed, cooperatively stimulated by LPS and effector-driven actin polymerization.
  • Tir-intimin signaling is essential and sufficient for EPEC-induced inflammasome activation, highlighting its importance in host-pathogen interactions.

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