Browse > Article
http://dx.doi.org/10.4142/jvs.2021.22.e39

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)
Publication Information
Journal of Veterinary Science / v.22, no.3, 2021 , pp. 39.18-39.18 More about this Journal
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
IFNLR1; PRRSV; replication; proliferation; cell cycle;
Citations & Related Records
연도 인용수 순위
  • Reference
1 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.   DOI
2 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.   DOI
3 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.   DOI
4 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.
5 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.   DOI
6 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.   DOI
7 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.   DOI
8 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.   DOI
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.   DOI
10 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.   DOI
11 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.   DOI
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.   DOI
13 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.   DOI
14 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.   DOI
15 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.   DOI
16 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.   DOI
17 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.   DOI
18 Cavanagh D. Nidovirales: a new order comprising Coronaviridae and Arteriviridae. Arch Virol. 1997;142(3):629-633.
19 Keffaber KK. Reproduction failure of unknown etiology. Am Assoc Swine Pract Newsl. 1989;1:1-9.
20 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.   DOI
21 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.   DOI
22 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.   DOI
23 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.   DOI
24 Davy C, Doorbar J. G2/M cell cycle arrest in the life cycle of viruses. Virology. 2007;368(2):219-226.   DOI
25 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.   DOI
26 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.   DOI
27 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.   DOI
28 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.   DOI
29 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.   DOI
30 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.   DOI
31 Bagga S, Bouchard MJ. Cell cycle regulation during viral infection. In Cell Cycle Control. Humana Press, New York, NY 2014;1170:165-227.
32 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.   DOI
33 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.   DOI
34 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.
35 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.   DOI
36 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.   DOI
37 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.   DOI
38 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.   DOI
39 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.   DOI
40 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.   DOI
41 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.   DOI
42 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.   DOI
43 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.   DOI
44 Wang R, Zhang YJ. Antagonizing interferon-mediated immune response by porcine reproductive and respiratory syndrome virus. BioMed Res Int. 2014;2014:315470.   DOI
45 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.   DOI
46 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.   DOI
47 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.   DOI
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.   DOI
49 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.   DOI
50 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.   DOI
51 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.
52 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.   DOI