Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus
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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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Virus-induced senescence appears to be a universal stress response in host cells and can be triggered by many virus species.
“VIS appears to be a universal stress response in host cells and can be induced by many different virus species.”
From COVID-19 and cellular senescence (2023) · cites this paper as [36]
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- Authors
- Martínez, I., García-Carpizo, V., Guijarro, T., García-Gomez, A., Navarro, D., Aranda, A., & Zambrano, A.
- Affiliations
- Instituto de Salud Carlos III (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Corresponding author
- Zambrano, Alberto
- Venue
- Virulence
- Publisher
- Informa UK Limited
- Published
- 2016-01-25
- Volume
- 7
- Issue
- 4
- Pages
- 427-442
- ISSN
- 2150-5594 (ISSN-L)
- 2150-5608
- PMC
- PMC4871660
- OpenAlex
- W2311703219
- Cited by
- 68
- References
- 78
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 9 · 2022: 11 · 2021: 10 · 2020: 7 · 2019: 6 · 2018: 2 · 2017: 3 · 2016: 2
- FWCI
- 4.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Virulence (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Topics
- Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- respiratory syncytial virus, DNA double-strand breaks, cellular senescence, DNA damage, oxidative stress, mitochondrial reactive oxygen species, TP53, ATM, p21, γH2AX, 53BP1, syncytia, respiratory epithelium, aging, N-acetylcysteine, viral infection
- MeSH terms
- A549 Cells, Acetylcysteine, Animals, Cell Line, DNA Damage, Glutathione, Histones, Humans, Cellular Senescence, Reactive Oxygen Species, Respiratory Syncytial Virus, Human, Respiratory Syncytial Virus Infections, Oxidative Stress, Cyclin-Dependent Kinase Inhibitor p16, Respiratory Mucosa, Cyclin-Dependent Kinase Inhibitor p18, Mice, DNA Breaks, Double-Stranded, Host-Pathogen Interactions
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