DOI QR코드

DOI QR Code

Enhanced Viral Replication by Cellular Replicative Senescence

  • Ji-Ae Kim (Brain Korea 21 Plus for Biomedical Science, College of Medicine, Korea University) ;
  • Rak-Kyun Seong (Brain Korea 21 Plus for Biomedical Science, College of Medicine, Korea University) ;
  • Ok Sarah Shin (Brain Korea 21 Plus for Biomedical Science, College of Medicine, Korea University)
  • Received : 2016.09.04
  • Accepted : 2016.10.13
  • Published : 2016.10.31

Abstract

Cellular replicative senescence is a major contributing factor to aging and to the development and progression of aging-associated diseases. In this study, we sought to determine viral replication efficiency of influenza virus (IFV) and Varicella Zoster Virus (VZV) infection in senescent cells. Primary human bronchial epithelial cells (HBE) or human dermal fibroblasts (HDF) were allowed to undergo numbers of passages to induce replicative senescence. Induction of replicative senescence in cells was validated by positive senescence-associated b-galactosidase staining. Increased susceptibility to both IFV and VZV infection was observed in senescent HBE and HDF cells, respectively, resulting in higher numbers of plaque formation, along with the upregulation of major viral antigen expression than that in the non-senescent cells. Interestingly, mRNA fold induction level of virus-induced type I interferon (IFN) was attenuated by senescence, whereas IFN-mediated antiviral effect remained robust and potent in virus-infected senescent cells. Additionally, we show that a longevity-promoting gene, sirtuin 1 (SIRT1), has antiviral role against influenza virus infection. In conclusion, our data indicate that enhanced viral replication by cellular senescence could be due to senescence-mediated reduction of virus-induced type I IFN expression.

Keywords

Acknowledgement

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2016R1C1B2006493).

References

  1. van Deursen, J. M. 2014. The role of senescent cells in ageing. Nature 509: 439-446. 
  2. Hwang, E. S. 2002. Replicative senescence and senescence-like state induced in cancer-derived cells. Mech. Ageing Dev. 123: 1681-1694. 
  3. Campisi, J. 1997. The biology of replicative senescence. Eur. J. Cancer 33: 703-709. 
  4. Dorrington, M. G., and D. M. Bowdish. 2013. Immunosenescence and novel vaccination strategies for the elderly. Front. Immunol. 4: 171. 
  5. Reber, A. J., T. Chirkova, J. H. Kim, W. Cao, R. Biber, D. K. Shay, and S. Sambhara. 2012. Immunosenescence and challenges of vaccination against influenza in the aging population. Aging Dis. 3: 68-90. 
  6. Arvin, A. 2005. Aging, immunity, and the varicella-zoster virus. N. Engl. J. Med. 352: 2266-2267. 
  7. Levin, M. J., M. N. Oxman, J. H. Zhang, G. R. Johnson, H. Stanley, A. R. Hayward, M. J. Caulfield, M. R. Irwin, J. G. Smith, J. Clair, I. S. Chan, H. Williams, R. Harbecke, R. Marchese, S. E. Straus, A. Gershon, and A. Weinberg. 2008. Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine. J. Infect. Dis. 197: 825-835. 
  8. Panda, A., F. Qian, S. Mohanty, D. D. van, F. K. Newman, L. Zhang, S. Chen, V. Towle, R. B. Belshe, E. Fikrig, H. G. Allore, R. R. Montgomery, and A. C. Shaw. 2010. Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J. Immunol. 184: 2518-2527. 
  9. Wong, C. P., K. R. Magnusson, and E. Ho. 2010. Aging is associated with altered dendritic cells subset distribution and impaired proinflammatory cytokine production. Exp. Gerontol. 45: 163-169. 
  10. Shaw, A. C., D. R. Goldstein, and R. R. Montgomery. 2013. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13: 875-887. 
  11. Shaw, A. C., S. Joshi, H. Greenwood, A. Panda, and J. M. Lord. 2010. Aging of the innate immune system. Curr. Opin. Immunol. 22: 507-513. 
  12. Qian, F., X. Wang, L. Zhang, A. Lin, H. Zhao, E. Fikrig, and R. R. Montgomery. 2011. Impaired interferon signaling in dendritic cells from older donors infected in vitro with West Nile virus. J. Infect. Dis. 203: 1415-1424. 
  13. Baylis, D., D. B. Bartlett, H. P. Patel, and H. C. Roberts. 2013. Understanding how we age: insights into inflammaging. Longev. Healthspan 2: 8. 
  14. Haigis, M. C., and D. A. Sinclair. 2010. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5: 253-295. 
  15. Chen, H., Y. Wan, S. Zhou, Y. Lu, Z. Zhang, R. Zhang, F. Chen, D. Hao, X. Zhao, Z. Guo, D. Liu, and C. Liang. 2012. Endothelium-specific SIRT1 overexpression inhibits hyperglycemia-induced upregulation of vascular cell senescence. Sci. China Life Sci. 55: 467-473. 
  16. Koyuncu, E., H. G. Budayeva, Y. V. Miteva, D. P. Ricci, T. J. Silhavy, T. Shenk, and I. M. Cristea. 2014. Sirtuins are evolutionarily conserved viral restriction factors. MBio. 5. 
  17. Manicassamy, B., S. Manicassamy, A. Belicha-Villanueva, G. Pisanelli, B. Pulendran, and A. Garcia-Sastre. 2010. Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus. Proc. Natl. Acad. Sci. U. S. A. 107: 11531-11536. 
  18. Jeon, J. S., Y. H. Won, I. K. Kim, J. H. Ahn, O. S. Shin, J. H. Kim, and C. H. Lee. 2016. Analysis of single nucleotide polymorphism among varicella-zoster virus and identification of vaccine-specific sites. Virology 496: 277-286. 
  19. Choi, E. J., C. H. Lee, Y. C. Kim, O. S. Shin. 2015. Wogonin inhibits Varicella-Zoster (shingles) virus replication via modulation of type I interferon signaling and adenosine monophosphate-activated protein kinase activity. J. Funct. Foods 17: 399-409. 
  20. Kurz, D. J., S. Decary, Y. Hong, and J. D. Erusalimsky. 2000. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J. Cell Sci. 113 (Pt 20): 3613-3622. 
  21. Livak, K. J., and T. D. Schmittgen. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402-408. 
  22. Hayflick, L., and P. S. Moorhead. 1961. The serial cultivation of human diploid cell strains. Exp.Cell Res. 25: 585-621. 
  23. Moffat, J., H. Ito, M. Sommer, S. Taylor, and A. M. Arvin. 2002. Glycoprotein I of varicella-zoster virus is required for viral replication in skin and T cells. J. Virol. 76: 8468-8471. 
  24. Schneider, W. M., M. D. Chevillotte, and C. M. Rice. 2014. Interferon-stimulated genes: a complex web of host defenses. Annu. Rev. Immunol. 32: 513-545. 
  25. Ben-Porath, I., and R. A. Weinberg. 2005. The signals and pathways activating cellular senescence. Int. J. Biochem. Cell Biol. 37: 961-976. 
  26. Weiland, T., J. Lampe, F. Essmann, S. Venturelli, A. Berger, S. Bossow, S. Berchtold, K. Schulze-Osthoff, U. M. Lauer, and M. Bitzer. 2014. Enhanced killing of therapy-induced senescent tumor cells by oncolytic measles vaccine viruses. Int. J. Cancer 134: 235-243. 
  27. Kim, J. A., S. K. Park, M. Kumar, C. H. Lee, and O. S. Shin. 2015. Insights into the role of immunosenescence during varicella zoster virus infection (shingles) in the aging cell model. Oncotarget 6: 35324-35343. 
  28. Targonski, P. V., R. M. Jacobson, and G. A. Poland. 2007. Immunosenescence: role and measurement in influenza vaccine response among the elderly. Vaccine 25: 3066-3069. 
  29. Mitzel, D. N., V. Lowry, A. C. Shirali, Y. Liu, and H. W. Stout-Delgado. 2014. Age-enhanced endoplasmic reticulum stress contributes to increased Atg9A inhibition of STING-mediated IFN-beta production during Streptococcus pneumoniae infection. J. Immunol. 192: 4273-4283. 
  30. Kida, Y., and M. S. Goligorsky. 2016. Sirtuins, cell senescence, and vascular aging. Can. J. Cardiol. 32: 634-641. 
  31. Wang, T., H. Cui, N. Ma, and Y. Jiang. 2013. Nicotinamide-mediated inhibition of SIRT1 deacetylase is associated with the viability of cancer cells exposed to antitumor agents and apoptosis. Oncol. Lett. 6: 600-604. 
  32. Sauve, A. A., and V. L. Schramm. 2003. Sir2 regulation by nicotinamide results from switching between base exchange and deacetylation chemistry. Biochemistry 42: 9249-9256. 
  33. He, M., and S. J. Gao. 2014. A novel role of SIRT1 in gammaherpesvirus latency and replication. Cell Cycle 13: 3328-3330. 
  34. Pagans, S., A. Pedal, B. J. North, K. Kaehlcke, B. L. Marshall, A. Dorr, C. Hetzer-Egger, P. Henklein, R. Frye, M. W. McBurney, H. Hruby, M. Jung, E. Verdin, and M. Ott. 2005. SIRT1 regulates HIV transcription via Tat deacetylation. PLoS Biol. 3: e41.