羊口疮病毒与宿主的博弈:免疫应答与病毒免疫逃逸机制

doi:10.11843/j.issn.0366-6964.2023.05.008

摘要/Abstract

摘要： 羊口疮(orf)是由羊口疮病毒(orf virus, ORFV)感染引起的一种高度接触性、嗜上皮性人兽共患传染病,不但阻碍畜牧业发展,而且危害人类健康。ORFV感染诱导宿主强烈的免疫反应和炎症反应,但宿主仍可被ORFV反复感染,主要是因为ORFV在与宿主的长期相互作用过程中,发展和进化出多种免疫逃逸机制。ORFV主要通过抑制干扰素反应、抑制NF-κB信号通路、抑制炎症反应、调控细胞凋亡、细胞周期、自噬和血管增生等方式实现免疫逃逸。ORFV 免疫逃逸主要是通过其编码的多个免疫调控蛋白来实现。本文主要对ORFV感染引起的宿主免疫应答、ORFV免疫逃逸机制的最新研究进展进行综述,旨在为orf疫苗研制及综合防控提供重要参考。

关键词: 羊口疮, 羊口疮病毒, 免疫应答, 免疫逃逸机制, 免疫调控蛋白

Abstract: Contagious ecthyma, commonly known as orf, is a highly contagious and epitheliotropic zoonotic infectious disease caused by orf virus (ORFV), blocking the development of animal husbandry and threatening human health. Although ORFV infection can induce strong immune and inflammatory response, the host can be repeatedly infected. This is mainly because ORFV has developed and evolved multiple immune evasion mechanisms during the long-term interaction with the host. ORFV achieves immune evasion mainly by inhibiting interferon response, inhibiting NF-κB signaling pathway, inhibiting inflammatory response, regulating apoptosis, cell cycle, autophagy and vascular proliferation. The immune evasion of ORFV is mainly due to the multiple immunomodulatory proteins encoded by the virus. In this article, the latest research progress on host immune response against ORFV infection and the immune evasion mechanisms of ORFV are summarized, which provides ideas for orf vaccine development and comprehensive prevention and control of the disease.

Key words: orf, orf virus, immune response, immune evasion mechanisms, immunomodulatory protein

中图分类号:

S852.659.1

龙琴琴, 魏敏, 王雨婷, 文明, 庞峰. 羊口疮病毒与宿主的博弈:免疫应答与病毒免疫逃逸机制[J]. 畜牧兽医学报, 2023, 54(5): 1845-1853.

LONG Qinqin, WEI Min, WANG Yuting, WEN Ming, PANG Feng. The Battle between Orf Virus and Host: Immune Response and Viral Immune Evasion Mechanisms[J]. Acta Veterinaria et Zootechnica Sinica, 2023, 54(5): 1845-1853.

参考文献 64

[1]	KASSA T. A review on human orf:a neglected viral zoonosis[J]. Res Rep Trop Med, 2021, 12:153-172.
[2]	CHEN D X, WANG R X, LONG M J, et al. Identification of in vitro and in vivo oncolytic effect in colorectal cancer cells by orf virus strain NA1/11[J]. Oncol Rep, 2021, 45(2):535-546.
[3]	SAHU B P, MAJEE P, SINGH R R, et al. Recombination drives the emergence of orf virus diversity:evidence from the first complete genome sequence of an Indian orf virus isolate and comparative genomic analysis[J]. Arch Virol, 2022, 167(7):1571-1576.
[4]	KHALAFALLA A I, ELHAG A E, ISHAG H Z A. Field investigation and phylogenetic characterization of orf virus (ORFV) circulating in small ruminants and pseudocowpoxvirus (PCPV) in dromedary camels of eastern Sudan[J]. Heliyon, 2020, 6(3):e03595.
[5]	ZHOU Y L, GUAN J Y, LV L J, et al. Complete genomic sequences and comparative analysis of two orf virus isolates from Guizhou Province and Jilin province, China[J]. Virus Genes, 2022, 58(5):403-413.
[6]	CHEN H Q, LI W, KUANG Z Z, et al. The whole genomic analysis of orf virus strain HN3/12 isolated from Henan province, central China[J]. BMC Vet Res, 2017, 13(1):260:260.
[7]	VENKATESAN G, DE A K, ARYA S, et al. Molecular evidence and phylogenetic analysis of orf virus isolates from outbreaks in Tripura state of North-East India[J]. VirusDisease, 2018, 29(2):216-220.
[8]	SHEHATA A A, ELSHEIKH H A, ABD-ELFATAH E B. Molecular detection and characterization of orf virus from goats in Egypt[J]. Open Vet J, 2022, 12(2):273-280.
[9]	KARKI M, VENKATESAN G, KUMAR A, et al. Genetic analysis of two viroceptor genes of orf virus[J]. Arch Virol, 2022, 167(7):1577-1582.
[10]	YAO X T, PANG M, WANG T X, et al. Genomic features and evolution of the parapoxvirus during the past two decades[J]. Pathogens, 2020, 9(11):888.
[11]	WANG R X, WANG Y, LIU F, et al. Orf virus:a promising new therapeutic agent[J]. Rev Med Virol, 2019, 29(1):e2013.
[12]	庞峰, 龙琴琴, 程振涛. 羊口疮病毒编码的NF-κB抑制基因研究进展[J]. 中国兽医学报, 2022, 42(4):813-817, 823.PANG F, LONG Q Q, CHENG Z T. Research progress of NF-κB inhibitory gene encoded by orf virus[J]. Chinese Journal of Veterinary Science, 2022, 42(4):813-817, 823. (in Chinese)
[13]	张孟然, 丛潇, 顾月月, 等. 羊口疮病毒主要基因组编码蛋白及其功能[J]. 动物医学进展, 2022, 43(4):96-101.ZHANG M R, CONG X, GU Y Y, et al. Main genome coding proteins and functions of orf virus[J]. Progress in Veterinary Medicine, 2022, 43(4):96-101. (in Chinese)
[14]	BUKAR A M, JESSE F F A, ABDULLAH C A C, et al. Immunomodulatory strategies for parapoxvirus:current status and future approaches for the development of vaccines against orf virus infection[J]. Vaccines (Basel), 2021, 9(11):1341.
[15]	HAIG D M, MCINNES C J. Immunity and counter-immunity during infection with the parapoxvirus orf virus[J]. Virus Res, 2002, 88(1-2):3-16.
[16]	FLEMING S B, WISE L M, MERCER A A. Molecular genetic analysis of orf virus:a poxvirus that has adapted to skin[J]. Viruses, 2015, 7(3):1505-1539.
[17]	LLOYD J B, GILL H S, HAIG D M, et al. In vivo T-cell subset depletion suggests that CD4+ T-cells and a humoral immune response are important for the elimination of orf virus from the skin of sheep[J]. Vet Immunol Immunopathol, 2000, 74(3-4):249-262.
[18]	ANZILIERO D, WEIBLEN R, KREUTZ L C, et al. Inactivated Parapoxvirus ovis induces a transient increase in the expression of proinflammatory, Th1-related, and autoregulatory cytokines in mice[J]. Braz J Med Biol Res, 2014, 47(2):110-118.
[19]	HARVEY R, MCCAUGHAN C, WISE L M, et al. Orf virus inhibits interferon stimulated gene expression and modulates the JAK/STAT signalling pathway[J]. Virus Res, 2015, 208:180-188.
[20]	CESARO T, MICHIELS T. Inhibition of PKR by Viruses[J]. Front Microbiol, 2021, 12:757238.
[21]	CHUKWURAH E, FARABAUGH K T, GUAN B J, et al. A tale of two proteins:PACT and PKR and their roles in inflammation[J]. FEBS J, 2021, 288(22):6365-6391.
[22]	TSENG Y Y, LIN F Y, CHENG S F, et al. Functional analysis of the short isoform of orf virus protein OV20. 0[J]. J Virol, 2015, 89(9):4966-4979.
[23]	TSENG Y Y, LIAO G R, SEN G C, et al. Regulation of PACT-mediated protein kinase activation by the OV20. 0 protein of orf virus[J]. J Virol, 2015, 89(22):11619-11629.
[24]	LIAO G R, TSENG Y Y, TSENG C Y, et al. Adenosine deaminase acting on RNA 1 associates with orf virus OV20. 0 and enhances viral replication[J]. J Virol, 2019, 93(7):e01912-18.
[25]	ALDAIF B A, MERCER A A, FLEMING S B. The parapoxvirus orf virus inhibits IFN-β expression induced by dsRNA[J]. Virus Res, 2022, 307:198619.
[26]	YU H, LIN L B, ZHANG Z Q, et al. Targeting NF-κB pathway for the therapy of diseases:mechanism and clinical study[J]. Signal Transduct Target Ther, 2020, 5(1):209.
[27]	DENG L Y, ZENG Q R, WANG M S, et al. Suppression of NF-κB activity:a viral immune evasion mechanism[J]. Viruses, 2018, 10(8):409.
[28]	DIEL D G, DELHON G, LUO S, et al. A novel inhibitor of the NF-κB signaling pathway encoded by the parapoxvirus orf virus[J]. J Virol, 2010, 84(8):3962-3973.
[29]	LONG M J, WANG Y Y, CHEN D X, et al. Identification of host cellular proteins LAGE3 and IGFBP6 that interact with orf virus protein ORFV024[J]. Gene, 2018, 661:60-67.
[30]	DIEL D G, LUO S, DELHON G, et al. A nuclear inhibitor of NF-κB encoded by a poxvirus[J]. J Virol, 2011, 85(1):264-275.
[31]	CHEN D X, ZHENG Z W, XIAO B, et al. Orf virus 002 protein targets ovine protein S100A4 and inhibits NF-κB signaling[J]. Front Microbiol, 2016, 7:1389.
[32]	DIEL D G, LUO S, DELHON G, et al. Orf virus ORFV121 encodes a novel inhibitor of NF-κB that contributes to virus virulence[J]. J Virol, 2011, 85(5):2037-2049.
[33]	KHATIWADA S, DELHON G, NAGENDRAPRABHU P, et al. A parapoxviral virion protein inhibits NF-κB signaling early in infection[J]. PLoS Pathog, 2017, 13(8):e1006561.
[34]	NAGENDRAPRABHU P, KHATIWADA S, CHAULAGAIN S, et al. A parapoxviral virion protein targets the retinoblastoma protein to inhibit NF-κB signaling[J]. PLoS Pathog, 2017, 13(12):e1006779.
[35]	安雪珂. 羊口疮病毒编码的锚蛋白抑制NF-κB信号通路的分子机制研究[D]. 兰州:兰州大学, 2019.AN X K. Molecular mechanism of the inhibition of NF-κB signaling pathway by Ankyrin repeat proteins of orf virus[D]. Lanzhou:Lanzhou University, 2019. (in Chinese)
[36]	FLEMING S B, MCCAUGHAN C, LATEEF Z, et al. Deletion of the chemokine binding protein gene from the parapoxvirus Orf virus reduces virulence and pathogenesis in sheep[J]. Front Microbiol, 2017, 8:46.
[37]	MARTINS M, RODRIGUES F S, JOSHI L R, et al. Orf virus ORFV112, ORFV117 and ORFV127 contribute to ORFV IA82 virulence in sheep[J]. Vet Microbiol, 2021, 257:109066.
[38]	DEANE D, MCINNES C J, PERCIVAL A, et al. Orf virus encodes a novel secreted protein inhibitor of granulocyte-macrophage colony-stimulating factor and interleukin-2[J]. J Virol, 2000, 74(3):1313-1320.
[39]	DEANE D, UEDA N, WISE L M, et al. Conservation and variation of the parapoxvirus GM-CSF-inhibitory factor (GIF) proteins[J]. J Gen Virol, 2009, 90(Pt 4):970-977.
[40]	WISE L, MCCAUGHAN C, TAN C K, et al. Orf virus interleukin-10 inhibits cytokine synthesis in activated human THP-1 monocytes, but only partially impairs their proliferation[J]. J Gen Virol, 2007, 88(Pt 6):1677-1682.
[41]	BENNETT J R, LATEEF Z, FLEMING S B, et al. Orf virus IL-10 reduces monocyte, dendritic cell and mast cell recruitment to inflamed skin[J]. Virus Res, 2016, 213:230-237.
[42]	WISE L M, STUART G S, JONES N C, et al. Orf virus IL-10 and VEGF-E act synergistically to enhance healing of cutaneous wounds in mice[J]. J Clin Med, 2020, 9(4):1085.
[43]	HOSAMANI M, SCAGLIARINI A, BHANUPRAKASH V, et al. Orf:an update on current research and future perspectives[J]. Expert Rev Anti-Infect Ther, 2009, 7(7):879-893.
[44]	SURAWEERA C D, HINDS M G, KVANSAKUL M. Poxviral strategies to overcome host cell apoptosis[J]. Pathogens, 2020, 10(1):6.
[45]	WESTPHAL D, LEDGERWOOD E C, HIBMA M H, et al. A novel Bcl-2-like inhibitor of apoptosis is encoded by the parapoxvirus orf virus[J]. J Virol, 2007, 81(13):7178-7188.
[46]	WESTPHAL D, LEDGERWOOD E C, TYNDALL J D A, et al. The Orf virus inhibitor of apoptosis functions in a Bcl-2-like manner, binding and neutralizing a set of BH3-only proteins and active Bax[J]. Apoptosis, 2009, 14(11):1317-1330.
[47]	SURAWEERA C D, HINDS M G, KVANSAKUL M. Structural investigation of orf virus Bcl-2 homolog ORFV125 interactions with BH3-motifs from BH3-Only proteins Puma and Hrk[J]. Viruses, 2021, 13(7):1374.
[48]	王宪军, 向华, 张旭梅, 等. 羊口疮病毒ORFV118蛋白对山羊睾丸支持细胞周期、凋亡及免疫细胞因子的影响[J]. 华北农学报, 2022, 37(1):222-231.WANG X J, XIANG H, ZHANG X M, et al. Effects of ORFV118 on cell cycle, apoptosis and the immune-related cytokines in goat testicular sertoli cells[J]. Acta Agriculturae Boreali-Sinica, 2022, 37(1):222-231. (in Chinese)
[49]	LI W, CHEN H Q, DENG H, et al. Orf virus encoded protein ORFV119 induces cell apoptosis through the extrinsic and intrinsic pathways[J]. Front Microbiol, 2018, 9:1056.
[50]	陈慧芹. 羊口疮病毒119蛋白诱导细胞凋亡分子机制的研究[D]. 广州:南方医科大学, 2017.CHEN H Q. The molecular mechanisms of cell apoptosis induced by orf virus(ORFV)119 Protein[D]. Guangzhou:Southern Medical University, 2017. (in Chinese)
[51]	MO M, FLEMING S B, MERCER A A. Orf virus cell cycle regulator, PACR, competes with subunit 11 of the anaphase promoting complex for incorporation into the complex[J]. J Gen Virol, 2010, 91(Pt 12):3010-3015.
[52]	MO M, FLEMING S B, MERCER A A. Cell cycle deregulation by a poxvirus partial mimic of anaphase-promoting complex subunit 11[J]. Proc Natl Acad Sci U S A, 2009, 106(46):19527-19532.
[53]	LAN Y G, WANG G L, SONG D G, et al. Role of autophagy in cellular response to infection with orf virus Jilin isolate[J]. Vet Microbiol, 2016, 193:22-27.
[54]	吕丽君. 羊传染性脓疱病毒感染诱导OFTu细胞自噬的分子机制初步研究[D]. 长春:吉林大学, 2021.LV L J. Molecular mechanisms of autophagy induced by ORFV in OFTu cells[D]. Changchun:Jilin University, 2021. (in Chinese)
[55]	SAVORY L J, STACKER S A, FLEMING S B, et al. Viral vascular endothelial growth factor plays a critical role in orf virus infection[J]. J Virol, 2000, 74(22):10699-10706.
[56]	WISE L M, INDER M K, REAL N C, et al. The vascular endothelial growth factor (VEGF)-E encoded by orf virus regulates keratinocyte proliferation and migration and promotes epidermal regeneration[J]. Cell Microbiol, 2012, 14(9):1376-1390.
[57]	KARKI M, KUMAR A, ARYA S, et al. Circulation of orf viruses containing the NZ7-like vascular endothelial growth factor (VEGF-E) gene type in India[J]. Virus Res, 2020, 281:197908.
[58]	JIA H J, ZHAN L L, WANG X X, et al. Transcriptome analysis of sheep oral mucosa response to Orf virus infection[J]. PLoS One, 2017, 12(10):e0186681.
[59]	CHEN D X, LONG M J, XIAO B, et al. Transcriptomic profiles of human foreskin fibroblast cells in response to orf virus[J]. Oncotarget, 2017, 8(35):58668-58685.
[60]	PANG F, WANG X Y, CHEN Z, et al. Integrated analysis of differentially expressed miRNAs and mRNAs in goat skin fibroblast cells in response to Orf virus infection reveals that cfa-let-7a regulates thrombospondin 1 expression[J]. Viruses, 2020, 12(1):118.
[61]	PANG F, ZHANG M M, YANG X J, et al. Genome-wide analysis of circular RNAs in goat skin fibroblast cells in response to Orf virus infection[J]. PeerJ, 2019, 7:e6267.
[62]	庞峰. 羊口疮病毒感染影响宿主细胞circRNAs、mRNAs和miRNAs表达的研究[D]. 海口:海南大学, 2019.PANG F. The effects of orf virus infection on the expression of circRNAs, mRNAs and miRNAs in host cells[D]. Haikou:Hainan University, 2019. (in Chinese)
[63]	HAO J H, KONG H J, YAN M H, et al. Inhibition of orf virus replication in goat skin fibroblast cells by the HSPA1B protein, as demonstrated by iTRAQ-based quantitative proteome analysis[J]. Arch Virol, 2020, 165(11):2561-2587.
[64]	周荣云, 何珊, 朱美芹, 等. 天然免疫DNA模式识别受体的抗感染研究进展[J]. 中国动物传染病学报, 2018, 26(5):1-9.ZHOU R Y, HE S, ZHU M Q, et al. Advances of innate immune DNA recognition receptors against infection[J]. Chinese Journal of Animal Infectious Diseases, 2018, 26(5):1-9. (in Chinese)