Reactive oxygen species induced by Streptococcus pyogenes invasion trigger apoptotic cell death in infected epithelial cells

• Published in: Cellular microbiology Vol. 12; no. 6; pp. 814 - 830
• Main Authors: Aikawa, Chihiro, Nozawa, Takashi, Maruyama, Fumito, Tsumoto, Kohei, Hamada, Shigeyuki, Nakagawa, Ichiro
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.06.2010; Blackwell Publishing Ltd; Hindawi Limited
• Subjects: Apoptosis; Epithelial Cells - microbiology; HeLa Cells; Humans; rac1 GTP-Binding Protein - metabolism; Reactive Oxygen Species - metabolism; Reactive Oxygen Species - toxicity; Streptococcus pyogenes; Streptococcus pyogenes - pathogenicity
• ISSN: 1462-5814; 1462-5822
• DOI: 10.1111/j.1462-5822.2010.01435.x

Streptococcus pyogenes (group A streptococcus, GAS), one of the most common pathogens of humans, attaches and invades into human pharyngeal or skin epithelial cells. We have previously reported that induction of apoptosis is associated with GAS invasion, which induces mitochondrial dysfunction and apoptotic cell death. We demonstrate here that GAS-induced apoptosis is mediated by reactive oxygen species (ROS) production. Both the induction of apoptosis and ROS production markedly increased upon invasion of wild-type GAS strain JRS4 into HeLa cells; however, the apoptotic response was not observed in fibronectin-binding protein F1-disrupted mutant SAM1-infected cells. In Bcl-2-overexpressing HeLa cells (HBD98-2-4), the induction of apoptosis, ROS production and mitochondrial dysfunction were significantly suppressed, whereas the numbers of invaded GAS was not different between HeLa (mock cells) and the HeLa HBD98-2-4 cells. Whereas Rac1 activation occurred during GAS invasion, ROS production in GAS-infected cells was clearly inhibited by transfection with the Rac1 mutants (L37 or V12L37), but not by the dominant active mutant (V12L61) or by the dominant negative mutant (N17). These observations indicate that GAS invasion triggers ROS production through Rac1 activation and generated ROS induced mitochondrial dysfunction leading to cellular apoptosis.