title: Reactive oxygen species induced by Streptococcus pyogenes invasion trigger apoptotic cell death in infected epithelial cells.
abstract: 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.
authors.affiliation: Tokyo Medical and Dental University, Bunkyo-ku, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Aikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Nozawa
authors.forename: Fumito
authors.initials: F
authors.lastname: Maruyama
authors.forename: Kohei
authors.initials: K
authors.lastname: Tsumoto
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Hamada
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakagawa
mesh_terms: D017209:Apoptosis; D004847:Epithelial Cells / Q000382:microbiology*; D006367:HeLa Cells; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000633:toxicity*; D013297:Streptococcus pyogenes / Q000472:pathogenicity*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D020830:rac1 GTP-Binding Protein