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 two weeks in vivo. We show that influenza induces DNA damage 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 DSB repair proteins Ku70, Ku86 and Rad51 during the regenerative phase. In conclusion, results show that influenza induces DNA 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.

Zika Virus Infection Induces DNA Damage Response in Human Neural Progenitors That Enhances Viral Replication

“…Many viruses capable of modulating the host cell cycle employ the strategy of DDR induction; however, the mechanisms of DDR activation differ in their requirements for DNA damage. Some viral protein kinases can directly bind to components of the DDR pathway to activate downstream signaling cascades (28,29), while other viruses trigger (Continued on next page) the DDR by inducing physical breaks in host DNA (i.e., nicks and DSBs) or replication stress (30)(31)(32). Our work presented here suggests that ZIKV activates the DDR through the ATM/Chk2 checkpoint pathway by causing DSBs in DNA, revealing the mechanism by which ZIKV induces cell cycle perturbation and restricts the growth of hNPCs.…”

Unique Loss of the PYHIN Gene Family in Bats Amongst Mammals: Implications for Inflammasome Sensing

“…In addition, bats have been recognized to host and exhibit a co-evolutionary relationship with many zoonotic RNA and DNA viruses 25 . As viral genomic DNA 26 and host DNA damage induced by RNA viral infection 27 28 can activate inflammasomes, we cannot exclude the possibility that the increased or expanded exposure to these pathogens, as compared to terrestrial mammals which cannot or do not travel long distances, might have been an additional evolutionary driver for the loss of PYHIN genes. Alternatively, the abundance of such viruses detected in bats may be linked to a consequence of PYHIN deletion.…”

Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery from Influenza Infection

“…26 Our finding that ER stress is present in epithelial cells during recovery from influenza infection is consistent with the finding that DNA damage and apoptotic cells are also persistently increased after infection. 27 It is likely that persistent ER stress contributes to the epithelial metaplasia and honeycombing that is seen through 60 days after infection. It is known that parenchymal repair occurs through the migration of distal airway stem/ progenitor cells to sites of severe influenza injury.…”