Journal of Veterinary Science

The Korean Society of Veterinary Science (대한수의학회)
권호 표지
DOI QR코드

DOI QR Code

Role of IFNLR1 gene in PRRSV infection of PAM cells

  • Qin, Ming (Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University) ;
  • Chen, Wei (Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University) ;
  • Li, Zhixin (Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University) ;
  • Wang, Lixue (Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University) ;
  • Ma, Lixia (Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University) ;
  • Geng, Jinhong (Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University) ;
  • Zhang, Yu (Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University) ;
  • Zhao, Jing (Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University) ;
  • Zeng, Yongqing (Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University)
  • Received : 2021.02.04
  • Accepted : 2021.04.15
  • Published : 2021.05.31
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Interferon lambda receptor 1 (IFNLR1) is a type II cytokine receptor that clings to interleukins IL-28A, IL29B, and IL-29 referred to as type III IFNs (IFN-λs). IFN-λs act through the JAK-STAT signaling pathway to exert antiviral effects related to preventing and curing an infection. Although the immune function of IFN-λs in virus invasion has been described, the molecular mechanism of IFNLR1 in that process is unclear. Objectives: The purpose of this study was to elucidate the role of IFNLR1 in the pathogenesis and treatment of porcine reproductive and respiratory syndrome virus (PRRSV). Methods: The effects of IFNLR1 on the proliferation of porcine alveolar macrophages (PAMs) during PRRSV infection were investigated using interference and overexpression methods. Results: In this study, the expressions of the IFNLR1 gene in the liver, large intestine, small intestine, kidney, and lung tissues of Dapulian pigs were significantly higher than those in Landrace pigs. It was determined that porcine IFNLR1 overexpression suppresses PRRSV replication. The qRT-PCR results revealed that overexpression of IFNLR1 upregulated antiviral and IFN-stimulated genes. IFNLR1 overexpression inhibits the proliferation of PAMs and upregulation of p-STAT1. By contrast, knockdown of IFNLR1 expression promotes PAMs proliferation. The G0/G1 phase proportion in IFNLR1-overexpressing cells increased, and the opposite change was observed in IFNLR1-underexpressing cells. After inhibition of the JAK/STAT signaling pathway, the G2/M phase proportion in the IFNLR1-overexpressing cells showed a significant increasing trend. In conclusion, overexpression of IFNLR1 induces activation of the JAK/STAT pathway, thereby inhibiting the proliferation of PAMs infected with PRRSV. Conclusion: Expression of the IFNLR1 gene has an important regulatory role in PRRSV-infected PAMs, indicating it has potential as a molecular target in developing a new strategy for the treatment of PRRSV.

Keywords

Acknowledgement

This study was supported financially by the Agricultural Animal Breeding Project of Shandong Province (No. 2020LZGC012), Funds of Shandong "Double Tops" Program (No. SYL2017YSTD12), Shandong Modern Pig Technology & Industry System Project (No. SDAIT-08-02), Shandong Provincial Natural Science Foundation (No. ZR2018BC046, ZR2019MC053).

References

  1. Cavanagh D. Nidovirales: a new order comprising Coronaviridae and Arteriviridae. Arch Virol. 1997;142(3):629-633.
  2. Keffaber KK. Reproduction failure of unknown etiology. Am Assoc Swine Pract Newsl. 1989;1:1-9.
  3. Han J, Liu G, Wang Y, Faaberg KS. Identification of nonessential regions of the nsp2 replicase protein of porcine reproductive and respiratory syndrome virus strain VR-2332 for replication in cell culture. J Virol. 2007;81(18):9878-9890. https://doi.org/10.1128/JVI.00562-07
  4. Van Breedam W, Delputte PL, Van Gorp H, Misinzo G, Vanderheijden N, Duan X, et al. Porcine reproductive and respiratory syndrome virus entry into the porcine macrophage. J Gen Virol. 2010;91(Pt 7):1659-1667. https://doi.org/10.1099/vir.0.020503-0
  5. Meier WA, Galeota J, Osorio FA, Husmann RJ, Schnitzlein WM, Zuckermann FA. Gradual development of the interferon-γ response of swine to porcine reproductive and respiratory syndrome virus infection or vaccination. Virology. 2003;309(1):18-31. https://doi.org/10.1016/S0042-6822(03)00009-6
  6. Murtaugh MP, Xiao Z, Zuckermann F. Immunological responses of swine to porcine reproductive and respiratory syndrome virus infection. Viral Immunol. 2002;15(4):533-547. https://doi.org/10.1089/088282402320914485
  7. Qin M, Li C, Li Z, Chen W, Zeng Y. Genetic diversities and differentially selected regions between shandong indigenous pig breeds and western pig breeds. Front Genet. 2020;10:1351. https://doi.org/10.3389/fgene.2019.01351
  8. Innan H, Kim Y. Detecting local adaptation using the joint sampling of polymorphism data in the parental and derived populations. Genetics. 2008;179(3):1713-1720. https://doi.org/10.1534/genetics.108.086835
  9. Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003;4(1):69-77. https://doi.org/10.1038/ni875
  10. Witte K, Gruetz G, Volk HD, Looman AC, Asadullah K, Sterry W, et al. Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines. Genes Immun. 2009;10(8):702-714. https://doi.org/10.1038/gene.2009.72
  11. Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, et al. IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression. Am J Physiol Gastrointest Liver Physiol. 2005;289(5):G960-G968. https://doi.org/10.1152/ajpgi.00126.2005
  12. Maher SG, Sheikh F, Scarzello AJ, Romero-Weaver AL, Baker DP, Donnelly RP, et al. IFNalpha and IFNlambda differ in their antiproliferative effects and duration of JAK/STAT signaling activity. Cancer Biol Ther. 2008;7(7):1109-1115. https://doi.org/10.4161/cbt.7.7.6192
  13. Sommereyns C, Paul S, Staeheli P, Michiels T. IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog. 2008;4(3):e1000017. https://doi.org/10.1371/journal.ppat.1000017
  14. Wei L, Jing Z, Li-Peng G, Pu S, Zai-Xin L, Zeng-Jun LU, et al. Regulation of type III interferon response after rrsv infection of alveolar macrophages in pigs. Dongwu Yixue Jinzhan. 2019.
  15. Douam F, Soto Albrecht YE, Hrebikova G, Sadimin E, Davidson C, Kotenko SV, et al. Type III interferon-mediated signaling is critical for controlling live attenuated yellow fever virus infection in vivo. MBio. 2017;8(4):e00819-e17.
  16. Galani IE, Triantafyllia V, Eleminiadou EE, Koltsida O, Stavropoulos A, Manioudaki M, et al. Interferon-λ mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness. Immunity. 2017;46(5):875-890.e6. https://doi.org/10.1016/j.immuni.2017.04.025
  17. Cui Q, Zhang YX, Su J, Chen X, Ding K, Lei N, et al. Genetic variation in IL28RA is associated with the outcomes of HCV infection in a high-risk Chinese population. Infect Genet Evol. 2011;11(7):1682-1689. https://doi.org/10.1016/j.meegid.2011.06.016
  18. Jimenez-Sousa MA, Berenguer J, Fernandez-Rodriguez A, Micheloud D, Guzman-Fulgencio M, Miralles P, et al. IL28RA polymorphism (rs10903035) is associated with insulin resistance in HIV/HCV-coinfected patients. J Viral Hepat. 2014;21(3):189-197. https://doi.org/10.1111/jvh.12130
  19. Lazear HM, Daniels BP, Pinto AK, Huang AC, Vick SC, Doyle SE, et al. Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier. Sci Transl Med. 2015;7(284):284ra59-284ra59. https://doi.org/10.1126/scitranslmed.aaa4304
  20. Toettcher JE, Loewer A, Ostheimer GJ, Yaffe MB, Tidor B, Lahav G. Distinct mechanisms act in concert to mediate cell cycle arrest. Proc Natl Acad Sci U S A. 2009;106(3):785-790. https://doi.org/10.1073/pnas.0806196106
  21. Bagga S, Bouchard MJ. Cell cycle regulation during viral infection. In Cell Cycle Control. Humana Press, New York, NY 2014;1170:165-227.
  22. du Manoir JM, Albright BN, Stevenson G, Thompson SH, Mitchell GB, Clark ME, et al. Variability of neutrophil and pulmonary alveolar macrophage function in swine. Vet Immunol Immunopathol. 2002;89(3-4):175-186. https://doi.org/10.1016/S0165-2427(02)00207-6
  23. Zhou Z, Hamming OJ, Ank N, Paludan SR, Nielsen AL, Hartmann R. Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. J Virol. 2007;81(14):7749-7758. https://doi.org/10.1128/JVI.02438-06
  24. Taniguchi M, Yanagi Y, Ohno S. Both type I and type III interferons are required to restrict measles virus growth in lung epithelial cells. Arch Virol. 2019;164(2):439-446. https://doi.org/10.1007/s00705-018-4087-0
  25. Der SD, Zhou A, Williams BR, Silverman RH. Identification of genes differentially regulated by interferon α, β, or γ using oligonucleotide arrays. Proc Natl Acad Sci U S A. 1998;95(26):15623-15628. https://doi.org/10.1073/pnas.95.26.15623
  26. Katsounas A, Hubbard JJ, Wang CH, Zhang X, Dou D, Shivakumar B, et al. High interferon-stimulated gene ISG-15 expression affects HCV treatment outcome in patients co-infected with HIV and HCV. J Med Virol. 2013;85(6):959-963. https://doi.org/10.1002/jmv.23576
  27. Andrejeva J, Norsted H, Habjan M, Thiel V, Goodbourn S, Randall RE. ISG56/IFIT1 is primarily responsible for interferon-induced changes to patterns of parainfluenza virus type 5 transcription and protein synthesis. J Gen Virol. 2013;94(Pt 1):59-68. https://doi.org/10.1099/vir.0.046797-0
  28. Zheng S, Zhu D, Lian X, Liu W, Cao R, Chen P. Porcine 2', 5'-oligoadenylate synthetases inhibit Japanese encephalitis virus replication in vitro. J Med Virol. 2016;88(5):760-768. https://doi.org/10.1002/jmv.24397
  29. Vattem KM, Staschke KA, Wek RC. Mechanism of activation of the double-stranded-RNA-dependent protein kinase, PKR: role of dimerization and cellular localization in the stimulation of PKR phosphorylation of eukaryotic initiation factor-2 (eIF2). Eur J Biochem. 2001;268(13):3674-3684. https://doi.org/10.1046/j.1432-1327.2001.02273.x
  30. Shi H, Fu Q, Ren Y, Wang D, Qiao J, Wang P, et al. Both foot-and-mouth disease virus and bovine viral diarrhea virus replication are inhibited by Mx1 protein originated from porcine. Anim Biotechnol. 2015;26(1):73-79. https://doi.org/10.1080/10495398.2014.902850
  31. Mulupuri P, Zimmerman JJ, Hermann J, Johnson CR, Cano JP, Yu W, et al. Antigen-specific B-cell responses to porcine reproductive and respiratory syndrome virus infection. J Virol. 2008;82(1):358-370. https://doi.org/10.1128/JVI.01023-07
  32. Rovira A, Clement T, Christopher-Hennings J, Thompson B, Engle M, Reicks D, et al. Evaluation of the sensitivity of reverse-transcription polymerase chain reaction to detect porcine reproductive and respiratory syndrome virus on individual and pooled samples from boars. J Vet Diagn Invest. 2007;19(5):502-509. https://doi.org/10.1177/104063870701900507
  33. Bates JS, Petry DB, Eudy J, Bough L, Johnson RK. Differential expression in lung and bronchial lymph node of pigs with high and low responses to infection with porcine reproductive and respiratory syndrome virus. J Anim Sci. 2008;86(12):3279-3289. https://doi.org/10.2527/jas.2007-0685
  34. Jiang C, Xing F, Xing J, Jiang Y, Zhou E. Different expression patterns of PRRSV mediator genes in the lung tissues of PRRSV resistant and susceptible pigs. Dev Comp Immunol. 2013;39(1-2):127-131. https://doi.org/10.1016/j.dci.2012.01.003
  35. Liang W, Li Z, Wang P, Fan P, Zhang Y, Zhang Q, et al. Differences of immune responses between Tongcheng (Chinese local breed) and Large White pigs after artificial infection with highly pathogenic porcine reproductive and respiratory syndrome virus. Virus Res. 2016;215:84-93. https://doi.org/10.1016/j.virusres.2016.02.004
  36. Hu J, Yang D, Wang H, Li C, Zeng Y, Chen W. CpG oligodeoxynucleotides induce differential cytokine and chemokine gene expression profiles in dapulian and landrace pigs. Front Microbiol. 2016;7:1992.
  37. Liang W, Ji L, Zhang Y, Zhen Y, Zhang Q, Xu X, et al. Transcriptome differences in porcine alveolar macrophages from Tongcheng and Large White pigs in response to highly pathogenic porcine reproductive and respiratory syndrome virus (PRRSV) infection. Int J Mol Sci. 2017;18(7):1475. https://doi.org/10.3390/ijms18071475
  38. Davidson S, McCabe TM, Crotta S, Gad HH, Hessel EM, Beinke S, et al. IFNλ is a potent anti-influenza therapeutic without the inflammatory side effects of IFNα treatment. EMBO Mol Med. 2016;8(9):1099-1112. https://doi.org/10.15252/emmm.201606413
  39. Hernandez PP, Mahlakoiv T, Yang I, Schwierzeck V, Nguyen N, Guendel F, et al. Interferon-λ and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection. Nat Immunol. 2015;16(7):698-707. https://doi.org/10.1038/ni.3180
  40. Li L, Fu F, Xue M, Chen W, Liu J, Shi H, et al. IFN-lambda preferably inhibits PEDV infection of porcine intestinal epithelial cells compared with IFN-alpha. Antiviral Res. 2017;140:76-82. https://doi.org/10.1016/j.antiviral.2017.01.012
  41. Zhang D, Xia Q, Wu J, Liu D, Wang X, Niu Z. Construction and immunogenicity of DNA vaccines encoding fusion protein of murine complement C3d-p28 and GP5 gene of porcine reproductive and respiratory syndrome virus. Vaccine. 2011;29(4):629-635. https://doi.org/10.1016/j.vaccine.2010.11.046
  42. Yin X, Zhang S, Li B, Zhang Y, Zhang X. IL28RA inhibits human epidermal keratinocyte proliferation by inhibiting cell cycle progression. Mol Biol Rep. 2019;46(1):1189-1197. https://doi.org/10.1007/s11033-019-04586-0
  43. Davy C, Doorbar J. G2/M cell cycle arrest in the life cycle of viruses. Virology. 2007;368(2):219-226. https://doi.org/10.1016/j.virol.2007.05.043
  44. Schleimann MH, Hoberg S, Solhoj Hansen A, Bundgaard B, Witt CT, Kofod-Olsen E, et al. The DR6 protein from human herpesvirus-6B induces p53-independent cell cycle arrest in G2/M. Virology. 2014;452-453:254-263. https://doi.org/10.1016/j.virol.2014.01.028
  45. Song L, Han X, Jia C, Zhang X, Jiao Y, Du T, et al. 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. 2018;15(1):169. https://doi.org/10.1186/s12985-018-1081-9
  46. Groschel B, Bushman F. Cell cycle arrest in G2/M promotes early steps of infection by human immunodeficiency virus. J Virol. 2005;79(9):5695-5704. https://doi.org/10.1128/JVI.79.9.5695-5704.2005
  47. Dove B, Brooks G, Bicknell K, Wurm T, Hiscox JA. Cell cycle perturbations induced by infection with the coronavirus infectious bronchitis virus and their effect on virus replication. J Virol. 2006;80(8):4147-4156. https://doi.org/10.1128/JVI.80.8.4147-4156.2006
  48. Wang R, Nan Y, Yu Y, Yang Z, Zhang YJ. Variable interference with interferon signal transduction by different strains of porcine reproductive and respiratory syndrome virus. Vet Microbiol. 2013;166(3-4):493-503. https://doi.org/10.1016/j.vetmic.2013.07.022
  49. Wang R, Zhang YJ. Antagonizing interferon-mediated immune response by porcine reproductive and respiratory syndrome virus. BioMed Res Int. 2014;2014:315470. https://doi.org/10.1155/2014/315470
  50. Dumoutier L, Tounsi A, Michiels T, Sommereyns C, Kotenko SV, Renauld JC. Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-λ 1: similarities with type I interferon signaling. J Biol Chem. 2004;279(31):32269-32274. https://doi.org/10.1074/jbc.M404789200
  51. Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 2004;10(1):48-54. https://doi.org/10.1038/nm976
  52. Bai L, Fang H, Xia S, Zhang R, Li L, Ochando J, et al. STAT1 activation represses IL-22 gene expression and psoriasis pathogenesis. Biochem Biophys Res Commun. 2018;501(2):563-569. https://doi.org/10.1016/j.bbrc.2018.05.042