title: Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus.
abstract: Human respiratory syncytial virus (HRSV) accounts for the majority of lower respiratory tract infections during infancy and childhood and is associated with significant morbidity and mortality. HRSV provokes a proliferation arrest and characteristic syncytia in cellular systems such as immortalized epithelial cells. We show here that HRSV induces the expression of DNA damage markers and proliferation arrest such as P-TP53, P-ATM, CDKN1A and γH2AFX in cultured cells secondary to the production of mitochondrial reactive oxygen species (ROS). The DNA damage foci contained γH2AFX and TP53BP1, indicative of double-strand breaks (DSBs) and could be reversed by antioxidant treatments such as N-Acetylcysteine (NAC) or reduced glutathione ethyl ester (GSHee). The damage observed is associated with the accumulation of senescent cells, displaying a canonical senescent phenotype in both mononuclear cells and syncytia. In addition, we show signs of DNA damage and aging such as γH2AFX and CDKN2A expression in the respiratory epithelia of infected mice long after viral clearance. Altogether, these results show that HRSV triggers a DNA damage-mediated cellular senescence program probably mediated by oxidative stress. The results also suggest that this program might contribute to the physiopathology of the infection, tissue remodeling and aging, and might be associated to long-term consequences of HRSV infections.
authors.affiliation: a Department of Molecular Pathology , Spanish National Center for Microbiology, Institute of Health Carlos III , Madrid , Spain.
authors.forename: Isidoro
authors.initials: I
authors.lastname: Martínez
authors.affiliation: b Department of Endocrine Physiopathology and Nervous System , Institute for Biomedical Research (IIBM), CSIC-UAM , Madrid , Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: García-Carpizo
authors.affiliation: a Department of Molecular Pathology , Spanish National Center for Microbiology, Institute of Health Carlos III , Madrid , Spain.
authors.forename: Trinidad
authors.initials: T
authors.lastname: Guijarro
authors.affiliation: a Department of Molecular Pathology , Spanish National Center for Microbiology, Institute of Health Carlos III , Madrid , Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: García-Gomez
authors.affiliation: b Department of Endocrine Physiopathology and Nervous System , Institute for Biomedical Research (IIBM), CSIC-UAM , Madrid , Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Navarro
authors.affiliation: b Department of Endocrine Physiopathology and Nervous System , Institute for Biomedical Research (IIBM), CSIC-UAM , Madrid , Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Aranda
authors.affiliation: a Department of Molecular Pathology , Spanish National Center for Microbiology, Institute of Health Carlos III , Madrid , Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Zambrano
mesh_terms: D000072283:A549 Cells; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics*; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006657:Histones / Q000235:genetics; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000821:virology; D018357:Respiratory Syncytial Virus Infections / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000502:physiology*
chemical_list: C000614131:CDKN2A protein, human; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; C468783:H2AX protein, human; D006657:Histones; D017382:Reactive Oxygen Species; C475961:gamma-H2AX protein, mouse; C042431:S-ethyl glutathione; D005978:Glutathione; D000111:Acetylcysteine
keywords: DNA damage; ROS; cellular senescence; human respiratory; syncytial virus
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