Cytochrome c-mediated caspase-9 activation triggers apoptosis in Streptococcus pyogenes-infected epithelial cells

Cell Microbiol. 2001 Jun;3(6):395-405. doi: 10.1046/j.1462-5822.2001.00122.x.


Epithelial cells are the initial sites of host invasion by group A Streptococcus pyogenes (GAS), and their infection of epithelial cells has been suggested to induce apoptosis. However, the mechanism responsible for bacteria-host interaction and the induction of apoptosis has not been clearly understood. We demonstrate here that human pharyngeal epithelial HEp-2 cells became apoptotic with DNA fragmentation by invasion of GAS strains JRS4 (M6+, F1+) and JRS145 (M6-, F1+ mutant of JRS4), whereas apoptotic cellular changes were not observed in SAM1 (M6+, F1- mutant) or SAM2 (M6-, F1- mutant) infected HEp-2 cells. Confocal microscopy revealed that Bax translocation to mitochondria and cytochrome c release occurred after 4 h of infection. Western blot analyses showed that the amounts of Bcl-2 and Bcl-xL were decreased in the mitochondria of infected cells. In addition, we demonstrated that the release of nuclear histone from infected cells was prevented by the addition of caspase-9 inhibitor (Ac-LEHD-CHO). We conclude that the internalization of GAS in epithelial cells is necessary and sufficient for the induction of apoptosis, which is initiated by mitochondrial dysfunction, and the mechanism of GAS-induced apoptosis is clearly different from that induced by other intracellular invasive bacteria, e.g. Shigella and Salmonella species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cytochrome c Group / metabolism*
  • Enzyme Activation
  • Epithelial Cells / microbiology*
  • Humans
  • Pharyngeal Neoplasms
  • Streptococcus pyogenes / pathogenicity*
  • Tumor Cells, Cultured


  • Caspase Inhibitors
  • Cytochrome c Group
  • CASP9 protein, human
  • Caspase 9
  • Caspases