Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

Abstract

Streptococcus pneumoniaeis a leading cause of pneumonia and one of the most common causes of death globally. The impact ofS. pneumoniaeon host molecular processes that lead to detrimental pulmonary consequences is not fully understood. Here, we show thatS. pneumoniaeinduces 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 H2O2, 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 H2O2, greatly suppressesS. pneumoniae-induced DNA damage and apoptosis. Importantly,S. pneumoniaeinduces DSBs in the lungs of animals with acute pneumonia, and H2O2production byS. pneumoniaein 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 preventingS. pneumoniae-induced genotoxicity. Taken together, this study shows thatS. 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.