title: Influenza infection induces host DNA damage and dynamic DNA damage responses during tissue regeneration.
abstract: Influenza viruses account for significant morbidity worldwide. Inflammatory responses, including excessive generation of reactive oxygen and nitrogen species (RONS), mediate lung injury in severe influenza infections. However, the molecular basis of inflammation-induced lung damage is not fully understood. Here, we studied influenza H1N1 infected cells in vitro, as well as H1N1 infected mice, and we monitored molecular and cellular responses over the course of 2 weeks in vivo. We show that influenza induces DNA damage to both, when cells are directly exposed to virus in vitro (measured using the comet assay) and also when cells are exposed to virus in vivo (estimated via γH2AX foci). We show that DNA damage, as well as responses to DNA damage persist in vivo until long after virus has been cleared, at times when there are inflammation associated RONS (measured by xanthine oxidase activity and oxidative products). The frequency of lung epithelial and immune cells with increased γH2AX foci is elevated in vivo, especially for dividing cells (Ki-67-positive) exposed to oxidative stress during tissue regeneration. Additionally, we observed a significant increase in apoptotic cells as well as increased levels of DNA double strand break (DSB) repair proteins Ku70, Ku86 and Rad51 during the regenerative phase. In conclusion, results show that influenza induces DNA damage both in vitro and in vivo, and that DNA damage responses are activated, raising the possibility that DNA repair capacity may be a determining factor for tissue recovery and disease outcome.
authors: Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, #03-10/11 Innovation Wing, #03-12/13/14 Enterprise Wing, Singapore, 138602, Singapore.
authors: Na
authors: N
authors: Li
authors: Marcus
authors: M
authors: Parrish
authors: Tze Khee
authors: TK
authors: Chan
authors: Lu
authors: L
authors: Yin
authors: Prashant
authors: P
authors: Rai
authors: Yamada
authors: Y
authors: Yoshiyuki
authors: Nona
authors: N
authors: Abolhassani
authors: Kong Bing
authors: KB
authors: Tan
authors: Orsolya
authors: O
authors: Kiraly
authors: Vincent T K
authors: VT
authors: Chow
authors: Bevin P
authors: BP
authors: Engelward
mesh_terms: D000818:Animals; D002460:Cell Line; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004285:Dogs; D053118:Influenza A Virus, H1N1 Subtype; D008168:Lung / Q000503:physiopathology / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D009976:Orthomyxoviridae Infections / Q000235:genetics* / Q000503:physiopathology*; D018384:Oxidative Stress / Q000235:genetics; D011014:Pneumonia / Q000503:physiopathology / Q000821:virology; D012038:Regeneration / Q000235:genetics* / Q000502:physiology*