Streptococcus Pneumoniae Secretes Hydrogen Peroxide Leading to DNA Damage and Apoptosis in Lung Cells
Author(s)Rai, Prashant; Tay, Ian Jun Jie; Li, Na; Ackerman, Shelley; He, Fang; Kwang, Jimmy; Chow, Vincent T.; Engelward, Bevin P.; Parrish, Marcus Curtis; Tay, Jun Jie Ian; ... Show more Show less
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Streptococcus pneumoniae is a leading cause of pneumonia and one of the most common causes of death globally. The impact of S. pneumoniae on host molecular processes that lead to detrimental pulmonary consequences is not fully understood. Here, we show that S. pneumoniae induces toxic DNA double-strand breaks (DSBs) in human alveolar epithelial cells, as indicated by ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of histone H2AX and colocalization with p53-binding protein (53BP1). Furthermore, results show that DNA damage occurs in a bacterial contact-independent fashion and that Streptococcus pyruvate oxidase (SpxB), which enables synthesis of H[subscript 2]O[subscript 2], plays a critical role in inducing DSBs. The extent of DNA damage correlates with the extent of apoptosis, and DNA damage precedes apoptosis, which is consistent with the time required for execution of apoptosis. Furthermore, addition of catalase, which neutralizes H[subscript 2]O[subscript 2], greatly suppresses S. pneumoniae-induced DNA damage and apoptosis. Importantly, S. pneumoniae induces DSBs in the lungs of animals with acute pneumonia, and H[subscript 2]O[subscript 2] production by S. pneumoniae in vivo contributes to its genotoxicity and virulence. One of the major DSBs repair pathways is nonhomologous end joining for which Ku70/80 is essential for repair. We find that deficiency of Ku80 causes an increase in the levels of DSBs and apoptosis, underscoring the importance of DNA repair in preventing S. pneumoniae-induced genotoxicity. Taken together, this study shows that S. pneumoniae-induced damage to the host cell genome exacerbates its toxicity and pathogenesis, making DNA repair a potentially important susceptibility factor in people who suffer from pneumonia.
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering
Proceedings of the National Academy of Sciences
National Academy of Sciences (U.S.)
Rai, Prashant, Marcus Parrish, Ian Jun Jie Tay, Na Li, Shelley Ackerman, Fang He, Jimmy Kwang, Vincent T. Chow, and Bevin P. Engelward. “ Streptococcus Pneumoniae Secretes Hydrogen Peroxide Leading to DNA Damage and Apoptosis in Lung Cells .” Proc Natl Acad Sci USA 112, no. 26 (June 15, 2015): E3421–E3430.
Final published version