Membrane damage during Listeria monocytogenes infection triggers a caspase-7 dependent cytoprotective response

PLoS Pathog. 2012;8(7):e1002628. doi: 10.1371/journal.ppat.1002628. Epub 2012 Jul 12.

Abstract

The cysteine protease caspase-7 has an established role in the execution of apoptotic cell death, but recent findings also suggest involvement of caspase-7 during the host response to microbial infection. Caspase-7 can be cleaved by the inflammatory caspase, caspase-1, and has been implicated in processing and activation of microbial virulence factors. Thus, caspase-7 function during microbial infection may be complex, and its role in infection and immunity has yet to be fully elucidated. Here we demonstrate that caspase-7 is cleaved during cytosolic infection with the intracellular bacterial pathogen, Listeria monocytogenes. Cleavage of caspase-7 during L. monocytogenes infection did not require caspase-1 or key adaptors of the primary pathways of innate immune signaling in this infection, ASC, RIP2 and MyD88. Caspase-7 protected infected macrophages against plasma membrane damage attributable to the bacterial pore-forming toxin Listeriolysin O (LLO). LLO-mediated membrane damage could itself trigger caspase-7 cleavage, independently of infection or overt cell death. We also detected caspase-7 cleavage upon treatment with other bacterial pore-forming toxins, but not in response to detergents. Taken together, our results support a model where cleavage of caspase-7 is a consequence of toxin-mediated membrane damage, a common occurrence during infection. We propose that host activation of caspase-7 in response to pore formation represents an adaptive mechanism by which host cells can protect membrane integrity during infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Bacterial Toxins / metabolism
  • CARD Signaling Adaptor Proteins
  • Caspase 1 / metabolism
  • Caspase 7 / metabolism*
  • Cell Membrane / microbiology*
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism
  • Heat-Shock Proteins / metabolism
  • Hemolysin Proteins / metabolism
  • Listeria monocytogenes / immunology
  • Listeria monocytogenes / metabolism
  • Listeria monocytogenes / pathogenicity*
  • Listeriosis / enzymology*
  • Listeriosis / immunology
  • Listeriosis / pathology*
  • Macrophages / metabolism*
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88 / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Virulence Factors / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Bacterial Toxins
  • CARD Signaling Adaptor Proteins
  • Cytoskeletal Proteins
  • Heat-Shock Proteins
  • Hemolysin Proteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Pycard protein, mouse
  • Virulence Factors
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk2 protein, mouse
  • Caspase 7
  • Caspase 1
  • hlyA protein, Listeria monocytogenes