Reduction of infection by inhibiting mTOR pathway is associated with reversed repression of type I interferon by porcine reproductive and respiratory syndrome virus Free

Abstract

Type I interferons (IFNs) are critical in animal antiviral regulation. IFN-mediated signalling regulates hundreds of genes that are directly associated with antiviral, immune and other physiological responses. The signalling pathway mediated by mechanistic target of rapamycin (mTOR), a serine/threonine kinase regulated by IFNs, is key in regulation of cellular metabolism and was recently implicated in host antiviral responses. However, little is known about how animal type I IFN signalling coordinates immunometabolic reactions during antiviral defence. Here, using porcine reproductive and respiratory syndrome virus (PRRSV), we found that the genes in the mTOR signalling pathway were differently regulated in PRRSV-infected porcine alveolar macrophages at different activation statuses. Moreover, mTOR signalling regulated PRRSV infection in MARC-145 and primary porcine cells, in part, through modulating the production and signalling of type I IFNs. Taken together, we determined that the mTOR signalling pathway involves PRRSV infection and regulates expression and signalling of type I IFNs against viral infection. These findings suggest that the mTOR signalling pathway has a bi-directional loop with the type I IFN system and imply that some components in the mTOR signalling pathway can be utilized as targets for studying antiviral immunity and for designing therapeutic reagents.

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2017-06-01
2024-03-28
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References

  1. Takeuchi O, Akira S. Innate immunity to virus infection. Immunol Rev 2009; 227:75–86 [View Article][PubMed]
    [Google Scholar]
  2. Brubaker SW, Bonham KS, Zanoni I, Kagan JC. Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 2015; 33:257–290 [View Article][PubMed]
    [Google Scholar]
  3. Hoffmann HH, Schneider WM, Rice CM. Interferons and viruses: an evolutionary arms race of molecular interactions. Trends Immunol 2015; 36:124–138 [View Article][PubMed]
    [Google Scholar]
  4. de Weerd NA, Nguyen T. The interferons and their receptors—distribution and regulation. Immunol Cell Biol 2012; 90:483–491 [View Article][PubMed]
    [Google Scholar]
  5. Sang Y, Bergkamp J, Blecha F. Molecular evolution of the porcine type I interferon family: subtype-specific expression and antiviral activity. PLoS One 2014; 9:e112378 [View Article][PubMed]
    [Google Scholar]
  6. Pestka S. The interferons: 50 years after their discovery, there is much more to learn. J Biol Chem 2007; 282:20047–20051 [View Article][PubMed]
    [Google Scholar]
  7. Levy DE, Marié IJ, Durbin JE. Induction and function of type I and III interferon in response to viral infection. Curr Opin Virol 2011; 1:476–486 [View Article][PubMed]
    [Google Scholar]
  8. Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol 2014; 14:36–49 [View Article][PubMed]
    [Google Scholar]
  9. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 2014; 32:513–545 [View Article][PubMed]
    [Google Scholar]
  10. Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 2005; 5:375–386 [View Article][PubMed]
    [Google Scholar]
  11. Saleiro D, Platanias LC. Intersection of mTOR and STAT signaling in immunity. Trends Immunol 2015; 36:21–29 [View Article][PubMed]
    [Google Scholar]
  12. Saleiro D, Platanias LC. ULK1 in type I interferon response. Oncotarget 2015; 6:24586–24587 [View Article][PubMed]
    [Google Scholar]
  13. Zarogoulidis P, Lampaki S, Turner JF, Huang H, Kakolyris S et al. mTOR pathway: a current, up-to-date mini-review. Oncol Lett 2014; 8:2367–2370 [View Article][PubMed]
    [Google Scholar]
  14. Costa-Mattioli M, Sonenberg N. RAPping production of type I interferon in pDCs through mTOR. Nat Immunol 2008; 9:1097–1099 [View Article][PubMed]
    [Google Scholar]
  15. Livingstone M, Sikström K, Robert PA, Uzé G, Larsson O et al. Assessment of mTOR-dependent translational regulation of interferon stimulated genes. PLoS One 2015; 10:e0133482 [View Article][PubMed]
    [Google Scholar]
  16. Cao W, Manicassamy S, Tang H, Kasturi SP, Pirani A et al. Toll-like receptor–mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol 2008; 9:1157–1164 [View Article][PubMed]
    [Google Scholar]
  17. Kaur S, Lal L, Sassano A, Majchrzak-Kita B, Srikanth M et al. Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling. J Biol Chem 2007; 282:1757–1768 [View Article][PubMed]
    [Google Scholar]
  18. Kaur S, Sassano A, Dolniak B, Joshi S, Majchrzak-Kita B et al. Role of the Akt pathway in mRNA translation of interferon-stimulated genes. Proc Natl Acad Sci USA 2008; 105:4808–4813 [View Article][PubMed]
    [Google Scholar]
  19. Saleiro D, Mehrotra S, Kroczynska B, Beauchamp EM, Lisowski P et al. Central role of ULK1 in type I interferon signaling. Cell Rep 2015; 11:605–617 [View Article][PubMed]
    [Google Scholar]
  20. Lekmine F, Uddin S, Sassano A, Parmar S, Brachmann SM et al. Activation of the p70 S6 kinase and phosphorylation of the 4E-BP1 repressor of mRNA translation by type I interferons. J Biol Chem 2003; 278:27772–27780 [View Article][PubMed]
    [Google Scholar]
  21. Sang Y, Brichalli W, Rowland RR, Blecha F. Genome-wide analysis of antiviral signature genes in porcine macrophages at different activation statuses. PLoS One 2014; 9:e87613 [View Article][PubMed]
    [Google Scholar]
  22. Katholnig K, Linke M, Pham H, Hengstschläger M, Weichhart T. Immune responses of macrophages and dendritic cells regulated by mTOR signalling. Biochem Soc Trans 2013; 41:927–933 [View Article][PubMed]
    [Google Scholar]
  23. Gordon S. The role of the macrophage in immune regulation. Res Immunol 1998; 149:685–688 [View Article][PubMed]
    [Google Scholar]
  24. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci 2008; 13:453–461 [View Article][PubMed]
    [Google Scholar]
  25. Sang Y, Miller LC, Blecha F. Macrophage polarization in virus-host interactions. J Clin Cell Immunol 2015; 6: [View Article][PubMed]
    [Google Scholar]
  26. Weichhart T, Hengstschläger M, Linke M. Regulation of innate immune cell function by mTOR. Nat Rev Immunol 2015; 15:599–614 [View Article][PubMed]
    [Google Scholar]
  27. Sang Y, Rowland RR, Blecha F. Antiviral regulation in porcine monocytic cells at different activation states. J Virol 2014; 88:11395–11410 [View Article][PubMed]
    [Google Scholar]
  28. Lisi L, Aceto P, Navarra P, dello Russo C. mTOR kinase: a possible pharmacological target in the management of chronic pain. Biomed Res Int 2015; 2015:1–13 [View Article][PubMed]
    [Google Scholar]
  29. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22:159–168 [View Article][PubMed]
    [Google Scholar]
  30. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009; 7:e1000038 [View Article][PubMed]
    [Google Scholar]
  31. Choi YJ, Park YJ, Park JY, Jeong HO, Kim DH et al. Inhibitory effect of mTOR activator MHY1485 on autophagy: suppression of lysosomal fusion. PLoS One 2012; 7:e43418 [View Article][PubMed]
    [Google Scholar]
  32. Sun MX, Huang L, Wang R, Yu YL, Li C et al. Porcine reproductive and respiratory syndrome virus induces autophagy to promote virus replication. Autophagy 2012; 8:1434–1447 [View Article][PubMed]
    [Google Scholar]
  33. Duan X, Nauwynck HJ, Pensaert MB. Effects of origin and state of differentiation and activation of monocytes/macrophages on their susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV). Arch Virol 1997; 142:2483–2497 [View Article][PubMed]
    [Google Scholar]
  34. Sang Y, Rowland RR, Blecha F. Interaction between innate immunity and porcine reproductive and respiratory syndrome virus. Anim Health Res Rev 2011; 12:149–167 [View Article][PubMed]
    [Google Scholar]
  35. Huang C, Zhang Q, Feng WH. Regulation and evasion of antiviral immune responses by porcine reproductive and respiratory syndrome virus. Virus Res 2015; 202:101–111 [View Article][PubMed]
    [Google Scholar]
  36. Lunney JK, Fang Y, Ladinig A, Chen N, Li Y et al. Porcine reproductive and respiratory syndrome virus (PRRSV): pathogenesis and interaction with the immune system. Annu Rev Anim Biosci 2016; 4:129–154 [View Article][PubMed]
    [Google Scholar]
  37. Sang Y, Rowland RR, Hesse RA, Blecha F. Differential expression and activity of the porcine type I interferon family. Physiol Genomics 2010; 42:248–258 [View Article][PubMed]
    [Google Scholar]
  38. Sang Y, Rowland RR, Blecha F. Porcine type I interferons: polymorphic sequences and activity against PRRSV. BMC Proc 2011; 5:S8 [View Article][PubMed]
    [Google Scholar]
  39. Schnorr JJ, Schneider-Schaulies S, Simon-Jödicke A, Pavlovic J, Horisberger MA et al. MxA-dependent inhibition of measles virus glycoprotein synthesis in a stably transfected human monocytic cell line. J Virol 1993; 67:4760–4768[PubMed]
    [Google Scholar]
  40. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14:1296–1302 [View Article][PubMed]
    [Google Scholar]
  41. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110:177–189 [View Article][PubMed]
    [Google Scholar]
  42. Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci 2009; 122:3589–3594 [View Article][PubMed]
    [Google Scholar]
  43. Loving CL, Brockmeier SL, Sacco RE. Differential type I interferon activation and susceptibility of dendritic cell populations to porcine arterivirus. Immunology 2007; 120:217–229 [View Article][PubMed]
    [Google Scholar]
  44. Sang Y, Shi J, Sang W, Rowland RR, Blecha F. Replication-competent recombinant porcine reproductive and respiratory syndrome (PRRS) viruses expressing indicator proteins and antiviral cytokines. Viruses 2012; 4:102–116 [View Article][PubMed]
    [Google Scholar]
  45. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA et al. Genome engineering using the CRISPR-Cas9 system. Nat Protoc 2013; 8:2281–2308 [View Article][PubMed]
    [Google Scholar]
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