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 gH2AFX in cultured cells secondary to the production of mitochondrial reactive oxygen species (ROS). The DNA damage foci contained gH2AFX 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 gH2AFX 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.

BRD4 Couples NF-κB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection

“…Additionally, RSV replication induces cellular senescence via ROS and DNA double-strand breaks associated with the ATM-TP53 pathway in a mouse model (60). Interestingly, BRD4 controls double-stranded DNA damage responses through the ATM pathway.…”

Senescence in Health and Disease

“…In contrast, given that certain viruses depend on host cell proliferation for viral replication, it has also been postulated that cellular senescence may have evolved as a host anti-viral defense (Reddel, 2010). Viral infection can induce cellular senescence directly via inducing cell fusion (Chuprin et al, 2013) or DNA damage (Martinez et al, 2016), and perhaps indirectly via prolonged cytokine signaling (e.g. interferons and TNFa) with the induction of nearby ‘paracrine’ senescence (Acosta et al, 2013; Coppe et al, 2008).…”

Senescent cells: Living or dying is a matter of NK cells

“…Recent studies highlight the link between cytosolic DNA sensing and the induction of cellular senescence, stressing the pivotal role of the cGAS‐STING pathway, thus, providing the molecular basis for considering cellular senescence as a defense system against virus infection, as well as genomic/neoplastic insult . Accordingly, type I IFNs result protective against retrotransposition events and cells accumulating DNA damage produce endogenous IFN‐β and become senescent . Hence, it is reasonable that type I IFN signaling drives cellular response upon both virus infection and DNA damage to protect genome integrity, becoming actually a tumor suppressive mechanism.…”