Reactive oxygen species induced by Streptococcus pyogenes invasion trigger apoptotic cell death in infected epithelial cells |
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| Authors: | Chihiro Aikawa Takashi Nozawa Fumito Maruyama Kohei Tsumoto Shigeyuki Hamada Ichiro Nakagawa |
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| Institution: | 1. Section of Bacterial Pathogenesis, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1‐5‐45, Yushima, Bunkyo‐ku, Tokyo 113‐8510, Japan.;2. Division of Bacteriology, International Research Center for infectious Diseases, Institute of Medical Science, The University of Tokyo, 4‐6‐1, Shirokanedai, Minato‐ku, Tokyo, 108‐8639, Japan.;3. Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5‐1‐5, Kahiwanoha, Kashiwa, Chiba 277‐8562, Japan.;4. Divison of Information Biotechnology, Department of Bioinformation Engineering, Tokyo Institute of Technology School and Graduate School of Bioscience and Biotechnology, 4259 Nagatsuta‐cho, Midori‐ku, Yokohama, Kanagawa 226‐8501, Japan.;5. Research Collaboration Center on Emerging and Reemerging Infections (RCC‐ERI) 6F, Department of Medical Sciences, Ministry of Public Health, Tiwanon Road, Muang Nonthaburi 11000, Thailand. |
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| 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. |
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