Publication: Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus
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Identifiers
ISSN: 2150-5594
Publication date
2016
Authors
Martinez, Isidoro ISCIII 
Guijarro, Trinidad ISCIII
Garcia-Gomez, Ana Belen ISCIII
Zambrano, Alberto ISCIII
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Publisher
Taylor & Francis
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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.
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MeSH Terms
A549 Cells Acetylcysteine Animals Cell Line Cyclin-Dependent Kinase Inhibitor p16 Cyclin-Dependent Kinase Inhibitor p18 DNA Damage Glutathione Histones Humans Mice Oxidative Stress Reactive Oxygen Species Respiratory Mucosa Respiratory Syncytial Virus Infections Respiratory Syncytial Virus, Human Cellular Senescence DNA Breaks, Double-Stranded Host-Pathogen Interactions
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Bibliographic citation
Virulence. 2016 May 18;7(4):427-42.