Abstract
As a potential vectored vaccine, Newcastle disease virus (NDV) has been subject to various studies for vaccine development, while relatively little research has outlined the immunomodulatory effect of the virus in antigen presentation. To elucidate the key inhibitory factor in regulating the interaction of infected dendritic cells (DCs) and T cells, DCs were pretreated with the NDV vaccine strain LaSota as an inhibitor and stimulated with lipopolysaccharide (LPS) for further detection by enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunoblotting, and quantitative real-time polymerase chain reaction (qRT-PCR). The results revealed that NDV infection resulted in the inhibition of interleukin (IL)-12p40 in DCs through a p38 mitogen-activated protein kinase (MAPK)-dependent manner, thus inhibiting the synthesis of IL-12p70, leading to the reduction in T cell proliferation and the secretion of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-6 induced by DCs. Consequently, downregulated cytokines accelerated the infection and viral transmission from DCs to T cells. Furthermore, several other strains of NDV also exhibited inhibitory activity. The current study reveals that NDV can modulate the intensity of the innate–adaptive immune cell crosstalk critically toward viral invasion improvement, highlighting a novel mechanism of virus-induced immunosuppression and providing new perspectives on the improvement of NDV-vectored vaccine.
摘要
新城疫病毒作为一种极具潜力的疫苗载体,已被应用于多种疫苗的开发,但目前对于该病毒在抗原提呈中免疫调节作用的研究较少。为阐明新城疫病毒感染的树突状细胞与T淋巴细胞相互作用时的关键抑制因子,本研究将新城疫病毒疫苗LaSota株作为抑制剂对树突状细胞进行预处理,并用细菌脂多糖刺激树突状细胞的活化,通过采用酶联免疫吸附法(ELISA)、流式细胞术、免疫印迹和荧光定量聚合酶链式反应(qRT-PCR)检测相关指标的变化。结果表明,新城疫病毒感染通过p38丝裂原活化蛋白激酶(MAPK)依赖的方式抑制树突状细胞中白介素12p40(IL-12p40)亚基的表达,从而抑制IL-12的活性单位IL-12p70的合成,致使树突状细胞诱导的T细胞增殖和γ干扰素(IFN-γ)、肿瘤坏死因子α(TNF-α)和6型白介素(IL-6)分泌下降。同时,细胞因子的下调促进了新城疫病毒从树突状细胞向T淋巴细胞的传播。此外,不同毒力型的新城疫病毒均表现出抑制活性。综上所述,新城疫病毒可以调节多种免疫细胞互作的强度,从而促进病毒的增殖与传播。因此,本研究揭示了一种新城疫病毒的新型免疫抑制机制,同时也为新城疫病毒载体疫苗的改进提供了新的思路。
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All data generated during the current study are included within this paper and its supplementary information files.
References
Ayasoufi K, Pfaller CK, 2020. Seek and hide: the manipulating interplay of measles virus with the innate immune system. Curr Opin Virol, 41:18–30. https://doi.org/10.1016/j.coviro.2020.03.001
Baratin M, Foray C, Demaria O, et al., 2015. Homeostatic NF-κB signaling in steady-state migratory dendritic cells regulates immune homeostasis and tolerance. Immunity, 42(4):627–639. https://doi.org/10.1016/j.immuni.2015.03.003
Brady MT, MacDonald AJ, Rowan AG, et al., 2003. Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes. Eur J Immunol, 33(12):3448–3457. https://doi.org/10.1002/eji.200324251
Cardone M, Ikeda KN, Varano B, et al., 2015. HIV-1-induced impairment of dendritic cell cross talk with γδ T lymphocytes. J Virol, 89(9):4798–4808. https://doi.org/10.1128/JVI.03681-14
Chen DJ, Liu XW, Xu SK, et al., 2019. TNF-α induced by porcine reproductive and respiratory syndrome virus inhibits the replication of classical swine fever virus C-strain. Vet Microbiol, 234:25–33. https://doi.org/10.1016/j.vetmic.2019.05.007
Coughlin MM, Bellini WJ, Rota PA, 2013. Contribution of dendritic cells to measles virus induced immunosuppression. Rev Med Virol, 23(2):126–138. https://doi.org/10.1002/rmv.1735
de Witte L, de Vries RD, van der Vlist M, et al., 2008. DC-SIGN and CD150 have distinct roles in transmission of measles virus from dendritic cells to T-lymphocytes. PLoS Pathog, 4(4):e1000049. https://doi.org/10.1371/journal.ppat.1000049
Dienz O, Rud JG, Eaton SM, et al., 2012. Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lung. Mucosal Immunol, 5(3):258–266. https://doi.org/10.1038/mi.2012.2
Durai V, Murphy KM, 2016. Functions of murine dendritic cells. Immunity, 45(4):719–736. https://doi.org/10.1016/j.immuni.2016.10.010
Gao HW, Liu X, Sun W, et al., 2017. Total tanshinones exhibits anti-inflammatory effects through blocking TLR4 dimerization via the MyD88 pathway. Cell Death Dis, 8(8):e3004. https://doi.org/10.1038/cddis.2017.389
Gately MK, Desai BB, Wolitzky AG, et al., 1991. Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol, 147(3):874–882. https://doi.org/10.4049/jimmunol.147.3.874
Ghilas S, Ambrosini M, Cancel JC, et al., 2021. Natural killer cells and dendritic epidermal γδ T cells orchestrate type 1 conventional DC spatiotemporal repositioning toward CD8+ T cells. iScience, 24(9):103059–103083. https://doi.org/10.1016/j.isci.2021.103059
Gupta M, Lo MK, Spiropoulou CF, 2013. Activation and cell death in human dendritic cells infected with Nipah virus. Virology, 441(1):49–56. https://doi.org/10.1016/j.virol.2013.03.004
Hilligan KL, Ronchese F, 2020. Antigen presentation by dendritic cells and their instruction of CD4+ T helper cell responses. Cell Mol Immunol, 17(6):587–599. https://doi.org/10.1038/s41423-020-0465-0
Jiang KF, Guo S, Yang C, et al., 2018. Barbaloin protects against lipopolysaccharide (LPS)-induced acute lung injury by inhibiting the ROS-mediated PI3K/AKT/NF-κB pathway. Int Immunopharmacol, 64:140–150. https://doi.org/10.1016/j.intimp.2018.08.02
Kürten CHL, Deuß E, Lei YL, et al., 2020. Stimulierende und inhibierende Signalwege der APZ- und T-Zell-Interaktion sowie Einfluss von TLR-Agonisten auf APZ. HNO, 68(12): 916–921 (in German). https://doi.org/10.1007/s00106-020-00960-8
Li YC, Wu QX, Huang LL, et al., 2018. An alternative pathway of enteric PEDV dissemination from nasal cavity to intestinal mucosa in swine. Nat Commun, 9:3811. https://doi.org/10.1038/s41467-018-06056-w
Menon MB, Gropengießer J, Fischer J, et al., 2017. P38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection. Nat Cell Biol, 19(10):1248–1259. https://doi.org/10.1038/ncb3614
Nan FL, Zhang H, Nan WL, et al., 2021a. Lentogenic NDV V protein inhibits IFN responses and represses cell apoptosis. Vet Microbiol, 261:109181. https://doi.org/10.1016/j.vetmic.2021.109181
Nan FL, Zheng W, Nan WL, et al., 2021b. Newcastle disease virus inhibits the proliferation of T cells induced by dendritic cells in vitro and in vivo. Front Immunol, 11:619829. https://doi.org/10.3389/fimmu.2020.619829
Nie Y, Wang Z, Chai G, et al., 2019. Dehydrocostus lactone suppresses LPS-induced acute lung injury and macrophage activation through NF-κB signaling pathway mediated by p38 MAPK and Akt. Molecules, 24(8):1510. https://doi.org/10.3390/molecules24081510
Park JG, Oladunni FS, Rohaim MA, et al., 2021. Immunogenicity and protective efficacy of an intranasal live-attenuated vaccine against SARS-CoV-2. iScience, 24(9):102941. https://doi.org/10.1016/j.isci.2021.102941
Pulendran B, 2015. The varieties of immunological experience: of pathogens, stress, and dendritic cells. Annu Rev Immunol, 33:563–606. https://doi.org/10.1146/annurev-immunol-020711-075049
Qian G, Li YW, Ma H, et al., 2018. Peiminine protects against lipopolysaccharide-induced mastitis by inhibiting the AKT/NF-κB, ERK1/2 and p38 signaling pathways. Int J Mol Sci, 19(9):2637. https://doi.org/10.3390/ijms19092637
Qiu X, Fu Q, Meng C, et al., 2016. Newcastle disease virus V protein targets phosphorylated STAT1 to block IFN-I signaling. PLoS ONE, 11(2):e0148560. https://doi.org/10.1371/journal.pone.0148560
Rajmani RS, Gupta SK, Singh PK, et al., 2016. HN protein of Newcastle disease virus sensitizes HeLa cells to TNF-α-induced apoptosis by downregulating NF-κB expression. Arch Virol, 161(9):2395–2405. https://doi.org/10.1007/s00705-016-2923-7
Rescigno M, 2002. Dendritic cells and the complexity of microbial infection. Trends Microbiol, 10(9):425–431. https://doi.org/10.1016/s0966-842x(02)02425-3
Romanets-Korbut O, Kovalevska LM, Seya T, et al., 2016. Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response. Cell Mol Immunol, 13(6):828–838. https://doi.org/10.1038/cmi.2015.55
Ronet C, Hauyon-La Torre Y, Revaz-Breton M, et al., 2010. Regulatory B cells shape the development of Th2 immune responses in BALB/c mice infected with Leishmania major through IL-10 production. J Immunol, 184(2): 886–894. https://doi.org/10.4049/jimmunol.0901114
Schönrich G, Raftery MJ, 2015. Dendritic cells as Achilles’ heel and Trojan horse during varicella zoster virus infection. Front Microbiol, 6:417. https://doi.org/10.3389/fmicb.2015.00417
Schulz O, Edwards AD, Schito M, et al., 2000. CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity, 13(4):453–462. https://doi.org/10.1016/s1074-7613(00)00045-5
Shrestha B, You DH, Saravia J, et al., 2017. IL-4Rα on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection. J Leukoc Biol, 102(1): 153–161. https://doi.org/10.1189/jlb.4A1216-536R
Sun WN, Liu YH, Amanat F, et al., 2021. A Newcastle disease virus expressing a stabilized spike protein of SARS-CoV-2 induces protective immune responses. Nat Commun, 12:6197. https://doi.org/10.1038/s41467-021-26499-y
Sun YJ, Zheng H, Yu SQ, et al., 2019. Newcastle disease virus V protein degrades mitochondrial antiviral signaling protein to inhibit host type I interferon production via E3 ubiquitin ligase RNF5. J Virol, 93(18):e00322–19. https://doi.org/10.1128/jvi.00322-19
Tan L, Zhang YQ, Qiao CT, et al., 2018. NDV entry into dendritic cells through macropinocytosis and suppression of T lymphocyte proliferation. Virology, 518:126–135. https://doi.org/10.1016/j.virol.2018.02.011
van Panhuys N, 2016. TCR signal strength alters T-DC activation and interaction times and directs the outcome of differentiation. Front Immunol, 7:6. https://doi.org/10.3389/fimmu.2016.00006
Wonderlich ER, Wu WC, Normolle DP, et al., 2015. Macrophages and myeloid dendritic cells lose T cell-stimulating function in simian immunodeficiency virus infection associated with diminished IL-12 and IFN-α production. J Immunol, 195(7):3284–3292. https://doi.org/10.4049/jimmunol.1500683
Yang X, Arslan M, Liu XJ, et al., 2020. IFN-γ establishes interferon-stimulated gene-mediated antiviral state against Newcastle disease virus in chicken fibroblasts. Acta Biochim Biophys Sin, 52(3):268–280. https://doi.org/10.1093/abbs/gmz158
Yoshimura S, Bondeson J, Foxwell BMJ, et al., 2001. Effective antigen presentation by dendritic cells is NF-κB dependent: coordinate regulation of MHC, co-stimulatory molecules and cytokines. Int Immunol, 13(5):675–683. https://doi.org/10.1093/intimm/13.5.675
Zhang H, Nan FL, Li ZX, et al., 2019. Construction and immunological evaluation of recombinant Newcastle disease virus vaccines expressing highly pathogenic porcine reproductive and respiratory syndrome virus GP3/GP5 proteins in pigs. Vet Microbiol, 239:108490. https://doi.org/10.1016/j.vetmic.2019.108490
Zhang HL, Chen S, Zeng MC, et al., 2018. Apelin-13 administration protects against LPS-induced acute lung injury by inhibiting NF-κB pathway and NLRP3 inflammasome activation. Cell Physiol Biochem, 49(5):1918–1932. https://doi.org/10.1159/000493653
Acknowledgments
This work was supported by the Qingdao Postdoctoral Application Research Project (No. RZ2200001472), the Shandong Provincial Innovative Ability Improvement Project of Scientific and Technological Small and Medium-Size Enterprise (No. 2022TSGC1142), the Shandong Provincial Science and Technology Foundation (No. 2019JZZY011009), and the Qingdao Municipal Science and Technology Foundation (No. 20-2-3-4-nsh), China.
We thank Zhigao BU (Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China), Zhuang DING (College of Veterinary Medicine, Jilin University, Changchun, China), and Xusheng QIU (Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China) for kindly providing the viruses.
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Ningyi JIN, Bin WANG, Huijun LU, Fulong NAN, and Wenlong NAN: methodology, investigation, formal analysis, and writing–original draft. Xin YAN, Hui WANG, Shasha JIANG, Shuyun ZHANG, Zhongjie YU, Xianjuan ZHANG, He ZHANG, and Fengjun LIU: methodology, investigation, formal analysis, and validation. Jun LI, Xiaoqiong ZHOU, Delei NIU, Yiquan LI, Wei WANG, Ning SHI, Changzhan XIE, and Xiaoni CUI: investigation and formal analysis. Ningyi JIN, He ZHANG, Bin WANG, Huijun LU, and Fulong NAN: funding acquisition, conceptualization, supervision, writing–reviewing & editing, project administration, and data curation. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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Fulong NAN, Wenlong NAN, Xin YAN, Hui WANG, Shasha JIANG, Shuyun ZHANG, Zhongjie YU, Xianjuan ZHANG, Fengjun LIU, Jun LI, Xiaoqiong ZHOU, Delei NIU, Yiquan LI, Wei WANG, Ning SHI, Ningyi JIN, Changzhan XIE, Xiaoni CUI, He ZHANG, Bin WANG, and Huijun LU declare that they have no conflict of interest.
All institutional and national guidelines for the care and use of laboratory animals were followed. All experimental animal procedures were reviewed and approved by the releva nt institutional Ethical Committee of Qingdao University (Approval ID: 20210613C573620220916106).
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Nan, F., Nan, W., Yan, X. et al. Newcastle disease virus suppresses antigen presentation via inhibiting IL-12 expression in dendritic cells. J. Zhejiang Univ. Sci. B 25, 254–270 (2024). https://doi.org/10.1631/jzus.B2300134
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DOI: https://doi.org/10.1631/jzus.B2300134