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Influenza infection induces host DNA damage and dynamic DNA damage responses during tissue regeneration

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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.

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Abbreviations

εdA:

1, N6-Etheno-2′-deoxyadenosine

εdG:

1, N2-Etheno-2′-deoxyguanosine

8-OH-dG:

8-Hydroxy-deoxyguanosine

8-OH-G:

8-Hydroxyguanosine

AEII:

Alveolar epithelial type II cells

ATM:

Ataxia telangiectasia mutated

ATR:

ATM- and Rad-3 related

BER:

Base excision repair

BALF:

Bronchoalveolar lavage fluid

CCSP:

Club cell secretary protein

DDR:

DNA damage response

DSBs:

DNA double-strand breaks

DNA-PKcs:

DNA-dependent protein kinase catalytic subunit

HA:

Hemagglutinin

HR:

Homologous recombination

MDCK:

Madin–Darby canine kidney

MOI:

Multiplicity of infection

NHEJ:

Non-homologous end joining

NS1:

Non-structural protein 1

PI3K-like kinases:

Phosphatidylinositol-3-kinase-like kinases

Pro-SPC:

Pro-surfactant protein C

RONS:

Reactive oxygen and nitrogen species

SSBs:

DNA single strand breaks

XO:

Xanthine oxidase

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Acknowledgments

We thank M. C. Phoon and S. H. Lau for propagating influenza virus and technical assistance. This study was supported by the Singapore National Research Foundation (NRF) and administered by the Singapore–MIT Alliance for Research and Technology. The views expressed herein are solely the responsibility of the authors and do not necessarily represent the official views of NRF.

Conflict of interest

The authors declare no competing interests.

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Authors and Affiliations

  1. Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, #03-10/11 Innovation Wing, #03-12/13/14 Enterprise Wing, Singapore, 138602, Singapore

    Na Li, Tze Khee Chan, Lu Yin, Prashant Rai, Yamada Yoshiyuki & Orsolya Kiraly

  2. Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave., 16-743, Cambridge, MA, 02139, USA

    Marcus Parrish, Nona Abolhassani & Bevin P. Engelward

  3. Department of Microbiology, National University of Singapore, 5 Science Drive 2, Blk MD4, Level 3, Singapore, 117545, Singapore

    Na Li, Prashant Rai & Vincent T. K. Chow

  4. Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Clinical Research Center, MD11, 10 Medical Drive, Level 5, #05-09, Singapore, 117597, Singapore

    Tze Khee Chan

  5. Department of Pathology, Yong loo Lin School of Medicine, National University Health System and National University of Singapore, Lower Kent Ridge Road, Singapore, 119074, Singapore

    Kong Bing Tan

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  1. Na Li
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Li, N., Parrish, M., Chan, T.K. et al. Influenza infection induces host DNA damage and dynamic DNA damage responses during tissue regeneration. Cell. Mol. Life Sci. 72, 2973–2988 (2015). https://doi.org/10.1007/s00018-015-1879-1

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  • DOI: https://doi.org/10.1007/s00018-015-1879-1

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