Virus Genes

, Volume 55, Issue 4, pp 433–439 | Cite as

Signaling pathways involved in regulating apoptosis induction in host cells upon PRRSV infection

  • Lihong FanEmail author
Review Paper


Porcine reproductive and respiratory syndrome virus (PRRSV) is the etiologic agent of porcine reproductive and respiratory syndrome (PRRS), a devastating disease of swine that poses a serious threat to the swine industry worldwide. The induction of apoptosis in host cells is suggested to be the key cellular mechanism that contributes to the pathogenesis of PRRS. Various signaling pathways have been identified to be involved in regulating PRRSV-induced apoptosis. In this review, we summarize the potential signaling pathways that contribute to PRRSV-induced apoptosis, and propose the issues that need to be addressed in future studies for a better understanding of the molecular basis underlying the pathogenesis of PRRS.


PRRSV Apoptosis Signaling pathways Mitochondrial pathway Death receptor pathway 



This work was funded by grants from National Natural Science Foundation of China (NSFC, 31671945).

Compliance with ethical standards

Conflicts of interest

The author has no conflicts of interest to disclosure.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Research involving human participants and/or animals

This is a review article and the article does not contain any studies with human participants or animals performed by the author.


  1. 1.
    Galluzzi L, Maiuri MC, Vitale I, Zischka H, Castedo M, Zitvogel L et al (2007) Cell death modalities: classification and pathophysiological implications. Cell Death Differ 14:1237–12343CrossRefPubMedGoogle Scholar
  2. 2.
    Peter ME (2011) Programmed cell death: apoptosis meets necrosis. Nature 471:310–312CrossRefPubMedGoogle Scholar
  3. 3.
    Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Kroemer G, Levine B (2008) Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 9:1004–1010CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Shen HM, Codogno P (2011) Autophagic cell death: Loch Ness monster or endangered species? Autophagy 7:457–465CrossRefPubMedGoogle Scholar
  6. 6.
    Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ et al (2008) Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135:1311–1323CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Yuan J, Kroemer G (2010) Alternative cell death mechanisms in development and beyond. Genes Dev 24:2592–2602CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Zhivotovsky B, Kroemer G (2004) Apoptosis and genomic instability. Nat Rev Mol Cell Biol 5:752–762CrossRefPubMedGoogle Scholar
  9. 9.
    Green DR, Galluzzi L, Kroemer G (2014) Cell biology. Metabolic control of cell death. Science. 345:1250256CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Galluzzi L, Brenner C, Morselli E, Touat Z, Kroemer G (2008) Viral control of mitochondrial apoptosis. PLoS Pathog 4:e1000018CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Lunney JK, Benfield DA, Rowland RR (2010) Porcine reproductive and respiratory syndrome virus: an update on an emerging and re-emerging viral disease of swine. Virus Res 154:1–6CrossRefPubMedGoogle Scholar
  12. 12.
    Suárez P, Díaz-Guerra M, Prieto C, Esteban M, Castro JM, Nieto A et al (1996) Open reading frame 5 of porcine reproductive and respiratory syndrome virus as a cause of virus-induced apoptosis. J Virol 70(5):2876–2882PubMedPubMedCentralGoogle Scholar
  13. 13.
    Sur JH, Doster AR, Christian JS, Galeota JA, Wills RW, Zimmerman JJ et al (1998) Porcine reproductive and respiratory syndrome virus replicates in testicular germ cells, alters spermatogenesis, and induces germ cell death by apoptosis. J Virol 71(12):9170–9179Google Scholar
  14. 14.
    Labarque G, Van Gucht S, Nauwynck H, Van Reeth K, Pensaert M (2003) Apoptosis in the lungs of pigs infected with porcine reproductive and respiratory syndrome virus and associations with the production of apoptogenic cytokines. Vet Res 34(3):249–260CrossRefPubMedGoogle Scholar
  15. 15.
    Costers S, Lefebvre DJ, Delputte PL, Nauwynck HJ (2008) Porcine reproductive and respiratory syndrome virus modulates apoptosis during replication in alveolar macrophages. Arch Virol 153(8):1453–1465CrossRefPubMedGoogle Scholar
  16. 16.
    Wang G, Li L, Yu Y, Tu Y, Tong J, Zhang C et al (2016) Highly pathogenic porcine reproductive and respiratory syndrome virus infection and induction of apoptosis in bone marrow cells of infected piglets. J Gen Virol 97(6):1356–1361CrossRefPubMedGoogle Scholar
  17. 17.
    Guo J, Zhou M, Liu X, Pan Y, Yang R, Zhao Z et al (2018) Porcine IFI30 inhibits PRRSV proliferation and host cell apoptosis in vitro. Gene 649:93–98CrossRefPubMedGoogle Scholar
  18. 18.
    Suárez P (2000) Ultrastructural pathogenesis of the PRRS virus. Vet Res 31(1):47–55PubMedGoogle Scholar
  19. 19.
    Karniychuk UU, Saha D, Geldhof M, Vanhee M, Cornillie P, Van den Broeck WP et al (2011) orcine reproductive and respiratory syndrome virus (PRRSV) causes apoptosis during its replication in fetal implantation sites. Microb Pathog 51(3):194–202CrossRefPubMedGoogle Scholar
  20. 20.
    Novakovic P, Harding JC, Al-Dissi AN, Detmer SE (2017) Type 2 porcine reproductive and respiratory syndrome virus infection increases apoptosis at the maternal-fetal interface in late gestation pregnant gilts. PLoS ONE 12(3):e0173360CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Lee SM, Kleiboeker SB (2007) Porcine reproductive and respiratory syndrome virus induces apoptosis through a mitochondria-mediated pathway. Virology 365:419–434CrossRefPubMedGoogle Scholar
  22. 22.
    Pujhari S, Zakhartchouk AN (2016) Porcine reproductive and respiratory syndrome virus envelope (E) protein interacts with mitochondrial proteins and induces apoptosis. Arch Virol 161:1821–1830CrossRefPubMedGoogle Scholar
  23. 23.
    Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63CrossRefPubMedGoogle Scholar
  24. 24.
    Yuan S, Zhang N, Xu L, Zhou L, Ge X, Guo X et al (2016) Induction of apoptosis by the nonstructural protein 4 and 10 of porcine reproductive and respiratory syndrome virus. PLoS ONE 11:e0156518CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Yin S, Huo Y, Dong Y, Fan L, Yang H et al (2012) Activation of c-Jun NH(2)-terminal kinase is required for porcine reproductive and respiratory syndrome virus-induced apoptosis but not for virus replication. Virus Res 166:103–108CrossRefPubMedGoogle Scholar
  26. 26.
    Yang SH, Sharrocks AD, Whitmarsh AJ (2013) MAP kinase signalling cascades and transcriptional regulation. Gene 513:1–13CrossRefPubMedGoogle Scholar
  27. 27.
    Wei L, Zhu Z, Wang J, Liu J (2009) JNK and p38 mitogen-activated protein kinase pathways contribute to porcine circovirus type 2 infection. J Virol 83:6039–6047CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Nacken W, Anhlan D, Hrincius ER, Mostafa A, Wolff T, Sadewasser A et al (2014) Activation of c-jun N-terminal kinase upon influenza A virus (IAV) infection is independent of pathogen-related receptors but dependent on amino acid sequence variations of IAV NS1. J Virol 88:8843–8852CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Fung TS, Liu DX (2017) Activation of the c-Jun NH2-terminal kinase pathway by coronavirus infectious bronchitis virus promotes apoptosis independently of c-Jun. Cell Death Dis 8:3215CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lee YJ, Lee C (2012) Stress-activated protein kinases are involved in porcine reproductive and respiratory syndrome virus infection and modulate virus-induced cytokine production. Virology 427:80–89CrossRefPubMedGoogle Scholar
  31. 31.
    Huo Y, Fan L, Yin S, Dong Y, Guo X, Yang H et al (2013) Involvement of unfolded protein response, p53 and Akt in modulation of porcine reproductive and respiratory syndrome virus-mediated JNK activation. Virology 444:233–240CrossRefPubMedGoogle Scholar
  32. 32.
    Jing H, Fang L, Wang D, Ding Z, Luo R, Chen H (2014) Porcine reproductive and respiratory syndrome virus infection activates NOD2-RIP2 signal pathway in MARC-145 cells. Virology 458–459:162–171CrossRefGoogle Scholar
  33. 33.
    Liu Y, Du Y, Wang H, Du L, Feng WH (2017) Porcine reproductive and respiratory syndrome virus (PRRSV) up-regulates IL-8 expression through TAK-1/JNK/AP-1 pathways. Virology 506:64–72CrossRefPubMedGoogle Scholar
  34. 34.
    Wu J, Kaufman RJ (2006) From acute ER stress to physiological roles of the Unfolded Protein Response. Cell Death Differ 13:374–384CrossRefPubMedGoogle Scholar
  35. 35.
    Rao RV, Ellerby HM, Bredesen DE (2004) Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ 11:372–380CrossRefPubMedGoogle Scholar
  36. 36.
    Xu C, Bailly-Maitre B, Reed JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115:2656–2664CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Chen WY, Schniztlein WM, Calzada-Nova G, Zuckermann FA (2017) Genotype 2 strains of porcine reproductive and respiratory syndrome virus dysregulate alveolar macrophage cytokine production via the unfolded protein response. J Virol 100:100. CrossRefGoogle Scholar
  38. 38.
    Wang X, Hai C (2016) Novel insights into redox system and the mechanism of redox Regulation. Mol Biol Rep 43:607–628CrossRefPubMedGoogle Scholar
  39. 39.
    Yuan J, Zhang S, Zhang Y (2018) Nrf1 is paved as a new strategic avenue to prevent and treat cancer, neurodegenerative and other diseases. Toxicol Appl Pharmacol 360:273–283CrossRefPubMedGoogle Scholar
  40. 40.
    Lee C (2018) Therapeutic modulation of virus-induced oxidative stress via the Nrf2-dependent antioxidative pathway. Oxid Med Cell Longev 2018:6208067PubMedPubMedCentralGoogle Scholar
  41. 41.
    Yan Y, Xin A, Liu Q, Huang H, Shao Z, Zang Y (2015) Induction of ROS generation and NF-κB activation in MARC-145 cells by a novel porcine reproductive and respiratory syndrome virus in Southwest of China isolate. BMC Vet Res 11:232CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Yan M, Hou M, Liu J, Zhang S, Liu B, Wu X (2017) Regulation of iNOS-Derived ROS Generation by HSP90 and Cav-1 in Porcine Reproductive and Respiratory Syndrome Virus-Infected Swine Lung Injury. Inflammation 40:1236–1244CrossRefPubMedGoogle Scholar
  43. 43.
    Stukelj M, Toplak I, Svete AN (2013) Blood antioxidant enzymes (SOD, GPX), biochemical and haematological parameters in pigs naturally infected with porcine reproductive and respiratory syndrome virus. Pol J Vet Sci 16:369–376CrossRefPubMedGoogle Scholar
  44. 44.
    Schuler M, Green DR (2001) Mechanisms of p53-dependent apoptosis. Biochem Soc Trans 29(6):684–688CrossRefPubMedGoogle Scholar
  45. 45.
    Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P et al (2003) p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11(3):577–590CrossRefPubMedGoogle Scholar
  46. 46.
    Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M et al (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303(5660):1010–1014CrossRefPubMedGoogle Scholar
  47. 47.
    Kruiswijk F, Labuschagne CF, Vousden KH (2015) p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol 16:393–405CrossRefPubMedGoogle Scholar
  48. 48.
    Huo Y, Yin S, Yan M, Win S, Aung Than T, Aghajan M (2017) Protective role of p53 in acetaminophen hepatotoxicity. Free Radic Biol Med 106:111–117CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Garner E, Raj K (2007) Protective mechanisms of p53-p21-pRb proteins against DNA damage-induced cell death. Cell Cycle 7(3):277–282CrossRefPubMedGoogle Scholar
  50. 50.
    Borrás C, Gómez-Cabrera MC, Viña J (2011) The dual role of p53: DNA protection and antioxidant. Free Radic Res 45:643–652CrossRefPubMedGoogle Scholar
  51. 51.
    Song L, Han X, Jia C, Zhang X, Jiao Y, Du T et al (2018) Porcine reproductive and respiratory syndrome virus inhibits MARC-145 proliferation via inducing apoptosis and G2/M arrest by activation of Chk/Cdc25C and p53/p21 pathway. Virol J 15:169CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Klionsky DJ (2018) Why do we need to regulate autophagy (and how can we do it)? A cartoon depiction. Autophagy. 14(10):1661–1664CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Levine B, Kroemer G (2019) Biological functions of autophagy genes: a disease perspective. Cell 176(1–2):11–42CrossRefPubMedGoogle Scholar
  54. 54.
    Levine B, Yuan J (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115:2679–2688CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Ahmad L, Mostowy S, Sancho-Shimizu V (2018) Autophagy-virus interplay: from cell biology to human disease. Front Cell Dev Biol 6:155CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Chen Q, Fang L, Wang D, Wang S, Li P, Li M et al (2012) Induction of autophagy enhances porcine reproductive and respiratory syndrome virus replication. Virus Res 163(2):650–655CrossRefPubMedGoogle Scholar
  57. 57.
    Liu Q, Qin Y, Zhou L, Kou Q, Guo X, Ge X et al (2012) Autophagy sustains the replication of porcine reproductive and respiratory virus in host cells. Virology 429(2):136–147CrossRefPubMedGoogle Scholar
  58. 58.
    Sun MX, Huang L, Wang R, Yu YL, Li C, Li PP et al (2012) Porcine reproductive and respiratory syndrome virus induces autophagy to promote virus replication. Autophagy 8(10):1434–1447CrossRefPubMedGoogle Scholar
  59. 59.
    Pujhari S, Kryworuchko M, Zakhartchouk AN (2014) Role of phosphatidylinositol-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) signalling pathways in porcine reproductive and respiratory syndrome virus (PRRSV) replication. Virus Res 194:138–144CrossRefPubMedGoogle Scholar
  60. 60.
    Wang G, Yu Y, Tu Y, Tong J, Liu Y, Zhang C et al (2015) Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Infection Induced Apoptosis and Autophagy in Thymi of Infected Piglets. PLoS ONE 10(6):e0128292CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Zhou A, Li S, Khan FA, Zhang S (2016) Autophagy postpones apoptotic cell death in PRRSV infection through Bad-Beclin1 interaction. Virulence 7(2):98–109CrossRefPubMedGoogle Scholar
  62. 62.
    Li S, Zhou A, Wang J, Zhang S (2016) Interplay of autophagy and apoptosis during PRRSV infection of Marc145 cell. Infect Genet Evol 39:51–54CrossRefPubMedGoogle Scholar
  63. 63.
    Wang K, Li S, Worku T, Hao X, Yang L, Zhang S (2017) Rab11a is required for porcine reproductive and respiratory syndrome virus induced autophagy to promote viral replication. Biochem Biophys Res Commun 492(2):236–242CrossRefPubMedGoogle Scholar
  64. 64.
    Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2(7):489–501CrossRefPubMedGoogle Scholar
  65. 65.
    Jafari M, Ghadami E, Dadkhah T, Akhavan-Niaki H (2019) PI3K/AKT signaling pathway: erythropoiesis and beyond. J Cell Physiol 234(3):2373–2385CrossRefPubMedGoogle Scholar
  66. 66.
    Diehl N, Schaal H (2013) Make yourself at home: viral hijacking of the PI3K/Akt signaling pathway. Viruses 5(12):3192–3212CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Zhang H, Wang X (2010) A dual effect of porcine reproductive and respiratory syndrome virus replication on the phosphatidylinositol-3-kinase-dependent Akt pathway. Arch Virol 155(4):571–575CrossRefPubMedGoogle Scholar
  68. 68.
    Zhu L, Yang S, Tong W, Zhu J, Yu H, Zhou Y et al (2013) Control of the PI3K/Akt pathway by porcine reproductive and respiratory syndrome virus. Arch Virol 158(6):1227–1234CrossRefPubMedGoogle Scholar
  69. 69.
    Wang X, Zhang H, Abel AM, Young AJ, Xie L, Xie Z (2014) Role of phosphatidylinositol 3-kinase (PI3K) and Akt1 kinase in porcine reproductive and respiratory syndrome virus (PRRSV) replication. Arch Virol 159(8):2091–2096CrossRefPubMedGoogle Scholar
  70. 70.
    Ni B, Wen LB, Wang R, Hao HP, Huan CC, Wang X et al (2015) The involvement of FAK-PI3K-AKT-Rac1 pathway in porcine reproductive and respiratory syndrome virus entry. Biochem Biophys Res Commun 458(2):392–398CrossRefPubMedGoogle Scholar
  71. 71.
    Wang R, Wang X, Wu JQ, Ni B, Wen LB, Huang L et al (2016) Efficient porcine reproductive and respiratory syndrome virus entry in MARC-145 cells requires EGFR-PI3K-AKT-LIMK1-COFILIN signaling pathway. Virus Res 225:23–32CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Preventive Medicine, College of Veterinary MedicineChina Agricultural UniversityBeijingChina

Personalised recommendations