Virus and Autophagy: Enemies or Allies

  • José A. BogaEmail author
  • Zulema Pérez-Martínez
  • Ana Coto-Montes
  • Marta E. Alvarez-Argüelles
  • Russel J. Reiter
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


Viral infection is one of the several stimuli which trigger autophagy, a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. This process also plays a housekeeping role in removing misfolded or aggregated proteins and clearing damaged organelles. Virus-induced autophagy has a dual role since it may be beneficial to the host by eliminating intracellular pathogens or it may benefit some viruses, which have developed strategies to directly or indirectly subvert autophagy in order to promote different stages of the viral life cycle. The upregulation of both oxidative and endoplasmic reticulum stresses has been reported as a means by which virus-induced pathways trigger autophagy. In this chapter the relationships between autophagy and viral infection are considered.


Viral infection Autophagy 



Funding: This work was supported by project grants GRUPIN14-071 and GRUPIN14-099 from PCTI (Principado de Asturias) and FEDER funds (EU).


  1. 1.
    Galluzzi L, Pietrocola F, Levine B, Kroemer G. Metabolic control of autophagy. Cell. 2014;159:1263–76.CrossRefGoogle Scholar
  2. 2.
    Lamb CA, Yoshimori T, Tooze SA. The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol. 2013;14:759–74.CrossRefGoogle Scholar
  3. 3.
    Chiramel AI, Brady NR, Bartenschlager R. Divergent roles of autophagy in virus infection. Cells. 2013;2:83–104.CrossRefGoogle Scholar
  4. 4.
    Paulus GL, Xavier RJ. Autophagy and checkpoints for intracellular pathogen defense. Curr Opin Gastroenterol. 2015;31:14–23.CrossRefGoogle Scholar
  5. 5.
    Joubert PE, Werneke S, de la Calle C, Guivel-Benhassine F, Giodini A, Peduto L, Levine B, Schwartz O, Lenschow D, Albert ML. Chikungunya-induced cell death is limited by ER and oxidative stress-induced autophagy. Autophagy. 2012;8:1261–3.CrossRefGoogle Scholar
  6. 6.
    Joubert PE, Meiffren G, Grégoire IP, Pontini G, Richetta C, Flacher M, Azocar O, Vidalain PO, Vidal M, Lotteau V, Codogno P, Rabourdin-Combe C, Faure M. Autophagy induction by the pathogen receptor CD46. Cell Host Microbe. 2009;6:354–66.CrossRefGoogle Scholar
  7. 7.
    Denizot M, Varbanov M, Espert L, Robert-Hebmann V, Sagnier S, Garcia E, Curriu M, Mamoun R, Blanco J, Biard-Piechaczyk M. HIV-1 gp41 fusogenic function triggers autophagy in uninfected cells. Autophagy. 2008;4:998–1008.CrossRefGoogle Scholar
  8. 8.
    Espert L, Denizot M, Grimaldi M, Robert-Hebmann V, Gay B, Varbanov M, Codogno P, Biard-Piechaczyk M. Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. J Clin Invest. 2006;116:2161–72.CrossRefGoogle Scholar
  9. 9.
    Mikula I Jr, Pastoreková S, Mikula I Sr. Toll-like receptors in immune response to the viral infections. Acta Virol. 2010;54:231–45.CrossRefGoogle Scholar
  10. 10.
    Loo YM, Gale M Jr. Immune signaling by RIG-I-like receptors. Immunity. 2011;34:680–92.CrossRefGoogle Scholar
  11. 11.
    Fensteri V, Sen GC. Interferons and viral infections. Biofactors. 2009;35:14–20.CrossRefGoogle Scholar
  12. 12.
    Sadler AJ, Williams BR. Interferon-inducible antiviral effectors. Nat Rev Immunol. 2008;8:559–68.CrossRefGoogle Scholar
  13. 13.
    Gorbea C, Makar KA, Pauschinger M, Pratt G, Bersola JL, Varela J, David RM, Banks L, Huang CH, Li H, Schultheiss HP, Towbin JA, Vallejo JG, Bowles NE. A role for Toll-like receptor 3 variants in host susceptibility to enteroviral myocarditis and dilated cardiomyopathy. J Biol Chem. 2010;285:23208–23.CrossRefGoogle Scholar
  14. 14.
    Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science. 2007;315:1398–401.CrossRefGoogle Scholar
  15. 15.
    Into T, Inomata M, Takayama E, Takigawa T. Autophagy in regulation of Toll-like receptor signaling. Cell Signal. 2012;24:1150–62.CrossRefGoogle Scholar
  16. 16.
    Delgado MA, Deretic V. Toll-like receptors in control of immunological autophagy. Cell Death Differ. 2009;16:976–83.CrossRefGoogle Scholar
  17. 17.
    Shi CS, Kehrl JH. MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. J Biol Chem. 2008;283:33175–82.CrossRefGoogle Scholar
  18. 18.
    Lippai M, Lőw P. The role of the selective adaptor p62 and ubiquitin-like proteins in autophagy. Biomed Res Int. 2014;2014:832704.CrossRefGoogle Scholar
  19. 19.
    Orvedahl A, MacPherson S, Sumpter R Jr, Talloczy Z, Zou Z, Levine B. Autophagy protects against Sindbis virus infection of the central nervous system. Cell Host Microbe. 2010;7:115–27.CrossRefGoogle Scholar
  20. 20.
    B’chir W, Maurin AC, Carraro V, Averous J, Jousse C, Muranishi Y, Parry L, Stepien G, Fafournoux P, Bruhat A. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 2013;41:7683–99.CrossRefGoogle Scholar
  21. 21.
    Martinon F. The endoplasmic reticulum: a sensor of cellular stress that modulates immune responses. Microbes Infect. 2012;14:1293–300.CrossRefGoogle Scholar
  22. 22.
    Gade P, Ramachandran G, Maachani UB, Rizzo MA, Okada T, Prywes R, Cross AS, Mori K, Kalvakolanu DV. An IFN-γ-stimulated ATF6-C/EBP-β-signaling pathway critical for the expression of death associated protein kinase 1 and induction of autophagy. Proc Natl Acad Sci U S A. 2012;109:10316–21.CrossRefGoogle Scholar
  23. 23.
    Ke PY, Chen SS. Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro. J Clin Invest. 2011;121:37–56.CrossRefGoogle Scholar
  24. 24.
    Mohl BP, Tedbury PR, Griffin S, Harris M. Hepatitis C virus-induced autophagy is independent of the unfolded protein response. J Virol. 2012;86:10724–32.CrossRefGoogle Scholar
  25. 25.
    McLean JE, Wudzinska A, Datan E, Quaglino D, Zakeri Z. Flavivirus NS4A-induced autophagy protects cells against death and enhances virus replication. J Biol Chem. 2011;286:22147–59.CrossRefGoogle Scholar
  26. 26.
    Carpenter JE, Jackson W, Benetti L, Grose C. Autophagosome formation during varicella zoster virus infection following endoplasmic reticulum stress and the unfolded protein response. J Virol. 2011;85:9414–24.CrossRefGoogle Scholar
  27. 27.
    Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J. 2012;441:523–40.CrossRefGoogle Scholar
  28. 28.
    Kosmider B, Messier EM, Janssen WJ, Nahreini P, Wang J, Hartshorn KL, Mason RJ. Nrf2 protects human alveolar epithelial cells against injury induced by influenza A virus. Respir Res. 2012;13:43.CrossRefGoogle Scholar
  29. 29.
    Olagnier D, Peri S, Steel C, van Montfoort N, Chiang C, Beljanski V, Slifker M, He Z, Nichols CN, Lin R, Balachandran S, Hiscott J. Cellular oxidative stress response controls the antiviral and apoptotic programs in dengue virus-infected dendritic cells. PLoS Pathog. 2014;10:e1004566.CrossRefGoogle Scholar
  30. 30.
    Schaedler S, Krause J, Himmelsbach K, Carvajal-Yepes M, Lieder F, Klingel K, Nassal M, Weiss TS, Werner S, Hildt E. Hepatitis B virus induces expression of antioxidant response element-regulated genes by activation of Nrf2. J Biol Chem. 2010;285:41074–86.CrossRefGoogle Scholar
  31. 31.
    Munz C. Antigen processing by macroautophagy for MHC presentation. Front Immunol. 2011;2:42.CrossRefGoogle Scholar
  32. 32.
    Leung CS, Taylor GS. Nuclear shelter: the influence of subcellular location on the processing of antigens by macroautophagy. Autophagy. 2010;6:510–1.CrossRefGoogle Scholar
  33. 33.
    Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D, Tuschl T, Münz C. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science. 2005;307:593–6.CrossRefGoogle Scholar
  34. 34.
    English L, Chemali M, Duron J, Rondeau C, Laplante A, Gingras D, Alexander D, Leib D, Norbury C, Lippé R, Desjardins M. Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol. 2009;10:480–7.CrossRefGoogle Scholar
  35. 35.
    Miller S, Krijnse-Locker J. Modification of intracellular membrane structures for virus replication. Nat Rev Microbiol. 2008;6:363–74.CrossRefGoogle Scholar
  36. 36.
    Schlegel A, Giddings TH Jr, Ladinsky MS, Kirkegaard K. Cellular origin and ultrastructure of membranes induced during poliovirus infection. J Virol. 1996;70:6576–88.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Huang SC, Chang CL, Wang PS, Tsai Y, Liu HS. Enterovirus 71-induced autophagy detected in vitro and in vivo promotes viral replication. J Med Virol. 2009;81:1241–52.CrossRefGoogle Scholar
  38. 38.
    O’Donnell V, Pacheco JM, LaRocco M, Burrage T, Jackson W, Rodriguez LL, Borca MV, Baxt B. Foot-and-mouth disease virus utilizes an autophagic pathway during viral replication. Virology. 2011;410:142–50.CrossRefGoogle Scholar
  39. 39.
    Granato M, Santarelli R, Farina A, Gonnella R, Lotti LV, Faggioni A, Cirone M. Epstein-barr virus blocks the autophagic flux and appropriates the autophagic machinery to enhance viral replication. J Virol. 2014;88:12715–26.CrossRefGoogle Scholar
  40. 40.
    Wen HJ, Yang Z, Zhou Y, Wood C. Enhancement of autophagy during lytic replication by the Kaposi’s sarcoma-associated herpesvirus replication and transcription activator. J Virol. 2010;84:7448–58.CrossRefGoogle Scholar
  41. 41.
    Grégoire IP, Richetta C, Meyniel-Schicklin L, Borel S, Pradezynski F, Diaz O, Deloire A, Azocar O, Baguet J, Le Breton M, Mangeot PE, Navratil V, Joubert PE, Flacher M, Vidalain PO, André P, Lotteau V, Biard-Piechaczyk M, Rabourdin-Combe C, Faure M. IRGM is a common target of RNA viruses that subvert the autophagy network. PLoS Pathog. 2011;7:e1002422.CrossRefGoogle Scholar
  42. 42.
    Wang X, Hou L, Du J, Zhou L, Ge X, Guo X, Yang H. Capsid, membrane and NS3 are the major viral proteins involved in autophagy induced by Japanese encephalitis virus. Vet Microbiol. 2015;178:217–29.CrossRefGoogle Scholar
  43. 43.
    Li J, Liu Y, Wang Z, Liu K, Wang Y, Liu J, Ding H, Yuan Z. Subversion of cellular autophagy machinery by hepatitis B virus for viral envelopment. J Virol. 2011;85:6319–33.CrossRefGoogle Scholar
  44. 44.
    Jackson WT, Giddings TH Jr, Taylor MP, Mulinyawe S, Rabinovitch M, Kopito RR, Kirkegaard K. Subversion of cellular autophagosomal machinery by RNA viruses. PLoS Biol. 2005;3:e156.CrossRefGoogle Scholar
  45. 45.
    Fliss PM, Jowers TP, Brinkmann MM, Holstermann B, Mack C, Dickinson P, Hohenberg H, Ghazal P, Brune W. Viral mediated redirection of NEMO/IKKgamma to autophagosomes curtails the inflammatory cascade. PLoS Pathog. 2012;8:e1002517.CrossRefGoogle Scholar
  46. 46.
    Green AM, Beatty PR, Hadjilaou A, Harris E. Innate immunity to dengue virus infection and subversion of antiviral responses. J Mol Biol. 2014;426:1148–60.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • José A. Boga
    • 1
    • 2
    Email author
  • Zulema Pérez-Martínez
    • 1
    • 2
  • Ana Coto-Montes
    • 3
    • 2
  • Marta E. Alvarez-Argüelles
    • 1
    • 2
  • Russel J. Reiter
    • 4
  1. 1.Servicio de MicrobiologíaHospital Universitario Central de AsturiasOviedoSpain
  2. 2.Instituto de Investigación Sanitaria del Principado de AsturiasISPAOviedoSpain
  3. 3.Departamento de Morfología y Biología Celular, Universidad de OviedoOviedoSpain
  4. 4.Department of Cellular & Structural BiologyUT Health Science Center at San AntonioSan AntonioUSA

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