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

PLoS Pathog. 2009 Apr;5(4):e1000361. doi: 10.1371/journal.ppat.1000361. Epub 2009 Apr 3.


Legionella pneumophila (L. pneumophila), the causative agent of a severe form of pneumonia called Legionnaires' disease, replicates in human monocytes and macrophages. Most inbred mouse strains are restrictive to L. pneumophila infection except for the A/J, Nlrc4(-/-) (Ipaf(-/-)), and caspase-1(-/-) derived macrophages. Particularly, caspase-1 activation is detected during L. pneumophila infection of murine macrophages while absent in human cells. Recent in vitro experiments demonstrate that caspase-7 is cleaved by caspase-1. However, the biological role for caspase-7 activation downstream of caspase-1 is not known. Furthermore, whether this reaction is pertinent to the apoptosis or to the inflammation pathway or whether it mediates a yet unidentified effect is unclear. Using the intracellular pathogen L. pneumophila, we show that, upon infection of murine macrophages, caspase-7 was activated downstream of the Nlrc4 inflammasome and required caspase-1 activation. Such activation of caspase-7 was mediated by flagellin and required a functional Naip5. Remarkably, mice lacking caspase-7 and its macrophages allowed substantial L. pneumophila replication. Permissiveness of caspase-7(-/-) macrophages to the intracellular pathogen was due to defective delivery of the organism to the lysosome and to delayed cell death during early stages of infection. These results reveal a new mechanism for caspase-7 activation downstream of the Nlrc4 inflammasome and present a novel biological role for caspase-7 in host defense against an intracellular bacterium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / immunology*
  • Calcium-Binding Proteins / immunology*
  • Caspase 1 / metabolism
  • Caspase 7 / metabolism*
  • Cells, Cultured
  • Enzyme Activation
  • Flagellin / metabolism
  • Humans
  • Interleukin-18 / immunology
  • Interleukin-1beta / immunology
  • Legionella pneumophila / growth & development*
  • Legionella pneumophila / immunology*
  • Legionnaires' Disease / immunology*
  • Legionnaires' Disease / microbiology
  • Lysosomes / immunology
  • Macrophages / enzymology
  • Macrophages / immunology*
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / immunology
  • Neuronal Apoptosis-Inhibitory Protein / immunology
  • Signal Transduction / immunology*


  • Apoptosis Regulatory Proteins
  • Calcium-Binding Proteins
  • Interleukin-18
  • Interleukin-1beta
  • Ipaf protein, mouse
  • Naip5 protein, mouse
  • Neuronal Apoptosis-Inhibitory Protein
  • Flagellin
  • Caspase 7
  • Caspase 1