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Caspase-7 activation by the Nlrc4/Ipaf inflammasome restricts Legionella pneumophila infection

Anwari Akhter1, Mikhail A Gavrilin, Laura Frantz

  • 1Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Center for Microbial Interface Biology and the Department of Internal Medicine, Ohio State University, Columbus, OH, USA.

Plos Pathogens
|April 4, 2009
PubMed

Insights

Caspase-7 activation, downstream of caspase-1, is crucial for controlling Legionella pneumophila infection in mice. Lacking caspase-7 impairs macrophage defense, allowing bacterial replication.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • Legionella pneumophila causes Legionnaires' disease, replicating in human monocytes and macrophages.
  • Murine macrophages, unlike human cells, activate caspase-1 during L. pneumophila infection.
  • Caspase-7 cleavage by caspase-1 is known, but its biological role remains unclear.

Purpose of the Study:

  • To elucidate the biological role of caspase-7 activation downstream of caspase-1 during L. pneumophila infection.
  • To determine if caspase-7 activation relates to apoptosis, inflammation, or an unknown effect.
  • To investigate the mechanism of caspase-7 activation and its role in host defense.

Main Methods:

  • Infection of murine macrophages with L. pneumophila.
  • Analysis of caspase-7 activation downstream of the Nlrc4 inflammasome and caspase-1.
  • Assessment of L. pneumophila replication in caspase-7 deficient mice and macrophages.
  • Evaluation of lysosomal delivery and cell death in caspase-7 deficient macrophages.

Main Results:

  • Caspase-7 activation was observed downstream of the Nlrc4 inflammasome, requiring caspase-1, flagellin, and Naip5.
  • Mice lacking caspase-7 exhibited substantial L. pneumophila replication.
  • Caspase-7 deficient macrophages showed defective lysosomal delivery and delayed cell death.
  • A novel mechanism for caspase-7 activation and its role in host defense was revealed.

Conclusions:

  • Caspase-7 activation is a novel downstream event of the Nlrc4 inflammasome pathway.
  • Caspase-7 plays a critical role in host defense against intracellular bacterial pathogens like L. pneumophila.
  • Deficiency in caspase-7 compromises macrophage function, leading to increased bacterial permissiveness.

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