非洲猪瘟病毒免疫逃逸分子机制研究进展

doi:10.11843/j.issn.0366-6964.2022.07.005

摘要/Abstract

摘要： 非洲猪瘟(African swine fever，ASF)是由非洲猪瘟病毒(African swine fever virus，ASFV)感染猪引起的一种急性、烈性、高度接触性传染病，至今没有研发出安全有效的疫苗，一旦暴发会造成重大经济损失。ASFV在和宿主长期作用过程中，通过抑制干扰素和炎症反应，调节凋亡、自噬及细胞免疫等多种途径逃逸机体免疫反应促进自身复制，但具体的机制仍不完全清楚。ASFV复杂的免疫逃逸机制可能是阻碍有效疫苗研发的关键因素之一。借助生物信息学技术对ASFV的基因组和蛋白质组深入分析，筛选病毒的免疫调控关键基因和保护性抗原表位，将在ASFV免疫逃逸分子机制的研究与疫苗研发中发挥重要作用。本文主要对ASFV感染引起的免疫应答反应及可能的免疫逃逸机制研究进行概述，以期为ASF疫苗研制及综合防控提供思路。

关键词: 非洲猪瘟, 非洲猪瘟病毒, 免疫应答, 免疫逃逸, 疫苗研发

Abstract: African swine fever virus (ASFV) infection causes an acute, intense, and highly contagious disease known as African swine fever (ASF). ASF outbreaks cause significant economic losses since there is no safe and effective vaccine has been developed. During the long-term interaction with the host, ASFV evolves various routes, such as inhibition of interferon and inflammation responses, regulation of apoptosis, autophagy and cellular immunity, to escape host immune surveillance to promote its replication, but the specific mechanism is still not completely clear. The complex immune escape mechanisms of ASFV may be the key factors that impede the development of effective ASF vaccine. Bioinformatics method can be used to analyze the genome and proteome of ASFV to Screen the key genes for immune regulation and protective antigen epitopes of the virus, which will be helpful for the study of molecular mechanism of ASFV immune escape and ASF vaccine development. In this review, research progresses on ASFV infection induced immune responses and the potential immune escape mechanisms of ASFV are summarized, which provides ideas for ASF vaccine development and comprehensive prevention and control of the disease.

Key words: African swine fever, African swine fever virus, immune response, immune escape, vaccine development

中图分类号:

S852.659.1

赵旭阳, 靳家鑫, 路闻龙, 张帅, 黄丽, 张改平, 孙爱军, 庄国庆. 非洲猪瘟病毒免疫逃逸分子机制研究进展[J]. 畜牧兽医学报, 2022, 53(7): 2074-2082.

ZHAO Xuyang, JIN Jiaxin, LU Wenlong, ZHANG Shuai, HUANG Li, ZHANG Gaiping, SUN Aijun, ZHUANG Guoqing. Advances in the Molecular Mechanism of Immune Escape of African Swine Fever Virus[J]. Acta Veterinaria et Zootechnica Sinica, 2022, 53(7): 2074-2082.

参考文献 66

[1]	SALGUERO F J. Comparative pathology and pathogenesis of African swine fever infection in swine[J]. Front Vet Sci, 2020, 7:282.
[2]	孙爱军,王芮,朱潇静,等.非洲猪瘟相关检测及猪场生物安全防控研究进展[J].中国兽医学报, 2021, 41(5):1023-1030.SUN A J, WANG R, ZHU X J, et al. Review on African swine fever-associated detection and pig farm biosecurity control measurement development[J]. Chinese Journal of Veterinary Science, 2021, 41(5):1023-1030.(in Chinese)
[3]	GAUDREAULT N N, MADDEN D W, WILSON W C, et al. African swine fever virus:an emerging DNA arbovirus[J]. Front Vet Sci, 2020, 7:215.
[4]	ALEJO A, MATAMOROS T, GUERRA M, et al. A proteomic atlas of the African swine fever virus particle[J]. J Virol, 2018, 92(23):e01293-18.
[5]	SUN T W, YANG C L, KAO T T, et al. Host range and coding potential of eukaryotic giant viruses[J]. Viruses, 2020, 12(11):1337.
[6]	OZGEN A, MURATOGLU H, DEMIRBAG Z, et al. Construction and characterization of a recombinant invertebrate iridovirus[J]. Virus Res, 2014, 189:286-292.
[7]	DIXON L K, SÁNCHEZ-CORDÓN P J, GALINDO I, et al. Investigations of pro-and anti-apoptotic factors affecting African swine fever virus replication and pathogenesis[J]. Viruses, 2017, 9(9):241.
[8]	LAWLER C, BRADY G. Poxviral targeting of interferon regulatory factor activation[J]. Viruses, 2020, 12(10):1191.
[9]	DE PAIVA E ALMEIDA S C, DE OLIVEIRA V L, PARKHOUSE R M E. Impact on antibody responses of B-cell-restricted transgenic expression of a viral gene inhibiting activation of NF-κB and NFAT[J]. Arch Virol, 2015, 160(6):1477-1488.
[10]	ALONSO C, GALINDO I, CUESTA-GEIJO M A, et al. African swine fever virus-cell interactions:from virus entry to cell survival[J]. Virus Res, 2013, 173(1):42-57.
[11]	FRANZONI G, GRAHAM S P, GIUDICI S D, et al. Characterization of the interaction of African swine fever virus with monocytes and derived macrophage subsets[J]. Vet Microbiol, 2017, 198:88-98.
[12]	SALAS M L, ANDRÉS G. African swine fever virus morphogenesis[J]. Virus Res, 2013, 173(1):29-41.
[13]	LI D, YANG W P, LI L L, et al. African swine fever virus MGF-505-7R negatively regulates cGAS-STING-mediated signaling pathway[J]. J Immunol, 2021, 206(8):1844-1857.
[14]	LI J N, SONG J, KANG L, et al. pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production[J]. PLoS Pathog, 2021, 17(7):e1009733.
[15]	BARRADO-GIL L, DEL PUERTO A, GALINDO I, et al. African swine fever virus ubiquitin-conjugating enzyme is an immunomodulator targeting NF-κB activation[J]. Viruses, 2021, 13(6):1160.
[16]	LI D, ZHANG J, YANG W P, et al. African swine fever virus protein MGF-505-7R promotes virulence and pathogenesis by inhibiting JAK1-and JAK2-mediated signaling[J]. J Biol Chem, 2021, 297(5):101190.
[17]	DE OLIVEIRA V L, ALMEIDA S C P, SOARES H R, et al. A novel TLR3 inhibitor encoded by African swine fever virus (ASFV)[J]. Arch Virol, 2011, 156(4):597-609.
[18]	ZHU J J, RAMANATHAN P, BISHOP E A, et al. Mechanisms of African swine fever virus pathogenesis and immune evasion inferred from gene expression changes in infected swine macrophages[J]. PLoS One, 2019, 14(11):e0223955.
[19]	ESCRIBANO J M, GALINDO I, ALONSO C. Antibody-mediated neutralization of African swine fever virus:myths and facts[J]. Virus Res, 2013, 173(1):101-109.
[20]	OURA C A L, DENYER M S, TAKAMATSU H, et al. In vivo depletion of CD8+ T lymphocytes abrogates protective immunity to African swine fever virus[J]. J Gen Virol, 2005, 86(Pt 9):2445-2450.
[21]	CHEN X X, YANG J F, JI Y H, et al. Recombinant Newcastle disease virus expressing African swine fever virus protein 72 is safe and immunogenic in mice[J]. Virol Sin, 2016, 31(2):150-159.
[22]	王西西,陈青,陈鸿军,等.非洲猪瘟病毒免疫逃逸相关蛋白研究进展[J].病毒学报, 2018, 34(6):929-935.WANG X X, CHEN Q, CHEN H J, et al. Research progress on immune evasion proteins of African swine fever virus[J]. Chinese Journal of Virology, 2018, 34(6):929-935.(in Chinese)
[23]	RANDALL R E, GOODBOURN S. Interferons and viruses:an interplay between induction, signalling, antiviral responses and virus countermeasures[J]. J Gen Virol, 2008, 89(Pt 1):1-47.
[24]	FAN W H, JIAO P T, ZHANG H, et al. Inhibition of African swine fever virus replication by porcine type I and type II interferons[J]. Front Microbiol, 2020, 11:1203.
[25]	DIXON L K, ISLAM M, NASH R, et al. African swine fever virus evasion of host defences[J]. Virus Res, 2019, 266:25-33.
[26]	AFONSO C L, PICCONE M E, ZAFFUTO K M, et al. African swine fever virus multigene family 360 and 530 genes affect host interferon response[J]. J Virol, 2004, 78(4):1858-1864.
[27]	申超超,李国丽,张大俊,等.非洲猪瘟病毒MGF 360-9L基因序列分析、蛋白结构预测及亚细胞定位[J].畜牧兽医学报, 2020, 51(6):1371-1381.SHEN C C, LI G L, ZHANG D J, et al. Gene sequence analysis, protein structure prediction and subcellular localization of MGF 360-9L from African swine fever virus[J]. Acta Veterinaria et Zootechnica Sinica, 2020, 51(6):1371-1381.(in Chinese)
[28]	CORREIA S, VENTURA S, PARKHOUSE R M. Identification and utility of innate immune system evasion mechanisms of ASFV[J]. Virus Res, 2013, 173(1):87-100.
[29]	ZHUO Y S, GUO Z H, BA T T, et al. African swine fever virus MGF360-12L inhibits type I interferon production by blocking the interaction of importin α and NF-κB signaling pathway[J]. Virol Sin, 2021, 36(2):176-186.
[30]	LIU X L, AO D, JIANG S, et al. African swine fever virus A528R inhibits TLR8 mediated NF-κB activity by targeting p65 activation and nuclear translocation[J]. Viruses, 2021, 13(10):2046.
[31]	YANG K D, HUANG Q T, WANG R Y, et al. African swine fever virus MGF505-11R inhibits type I interferon production by negatively regulating the cGAS-STING-mediated signaling pathway[J]. Vet Microbiol, 2021, 263:109265.
[32]	GAO Q, YANG Y L, QUAN W P, et al. The African swine fever virus with MGF360 and MGF505 deleted reduces the apoptosis of porcine alveolar macrophages by inhibiting the NF-κB signaling pathway and interleukin-1β[J]. Vaccines (Basel), 2021, 9(11):1371.
[33]	谭星,庞晓燕,郝秀静,等.胞质DNA感受器cGAS的研究进展[J].中国免疫学杂志, 2021, 37(21):2569-2574, 2579.TAN X, PANG X Y, HAO X J, et al. Research progress in cytoplasmic DNA sensors cGAS[J]. Chinese Journal of Immunology, 2021, 37(21):2569-2574, 2579.(in Chinese)
[34]	WANG X X, WU J, WU Y T, et al. Inhibition of cGAS-STING-TBK1 signaling pathway by DP96R of ASFV China 2018/1[J]. Biochem Biophys Res Commun, 2018, 506(3):437-443.
[35]	GARCÍA-BELMONTE R, PÉREZ-NU'ÑEZ D, PITTAU M, et al. African swine fever virus Armenia/07 virulent strain controls interferon beta production through the cGAS-STING pathway[J]. J Virol, 2019, 93(12):e02298-18.
[36]	LIU H S, ZHU Z X, FENG T, et al. African swine fever virus E120R protein inhibits interferon beta production by interacting with IRF3 to block its activation[J]. J Virol, 2021, 95(18):e0082421.
[37]	MISKIN J E, ABRAMS C C, DIXON L K. African swine fever virus protein A238L interacts with the cellular phosphatase calcineurin via a binding domain similar to that of NFAT[J]. J Virol, 2000, 74(20):9412-9420.
[38]	GRANJA A G, NOGAL M L, HURTADO C, et al. The viral protein A238L inhibits TNF-α expression through a CBP/p300 transcriptional coactivators pathway[J]. J Immunol, 2006, 176(1):451-462.
[39]	GRANJA A G, PERKINS N D, REVILLA Y. Correction:A238L inhibits NF-ATc2, NF-κB, and c-Jun activation through a novel mechanism involving protein kinase C-θ-mediated up-regulation of the amino-terminal transactivation domain of p300[J]. J Immunol, 2015, 194(4):2032.
[40]	GRIGORIU S, BOND R, COSSIO P, et al. The molecular mechanism of substrate engagement and immunosuppressant inhibition of calcineurin[J]. PLoS Biol, 2013, 11(2):e1001492.
[41]	GRANJA A G, NOGAL M L, HURTADO C, et al. The viral protein A238L inhibits cyclooxygenase-2 expression through a nuclear factor of activated T cell-dependent transactivation pathway[J]. J Biol Chem, 2004, 279(51):53736-53746.
[42]	BORCA M V, O'DONNELL V, HOLINKA L G, et al. The L83L ORF of African swine fever virus strain Georgia encodes for a non-essential gene that interacts with the host protein IL-1β[J]. Virus Res, 2018, 249:116-123.
[43]	CARRASCOSA A L, BUSTOS M J, NOGAL M L, et al. Apoptosis induced in an early step of African swine fever virus entry into vero cells does not require virus replication[J]. Virology, 2002, 294(2):372-382.
[44]	DANTHI P. Enter the kill zone:initiation of death signaling during virus entry[J]. Virology, 2011, 411(2):316-324.
[45]	VALLEE I, TAIT S W G, POWELL P P. African swine fever virus infection of porcine aortic endothelial cells leads to inhibition of inflammatory responses, activation of the thrombotic state, and apoptosis[J]. J Virol, 2001, 75(21):10372-10382.
[46]	PORTUGAL R, LEITÃO A, MARTINS C. Apoptosis in porcine macrophages infected in vitro with African swine fever virus (ASFV) strains with different virulence[J]. Arch Virol, 2009, 154(9):1441-1450.
[47]	BANJARA S, CARIA S, DIXON L K, et al. Structural insight into African swine fever virus A179L-mediated inhibition of apoptosis[J]. J Virol, 2017, 91(6):e02228-16.
[48]	BARBER C, NETHERTON C, GOATLEY L, et al. Identification of residues within the African swine fever virus DP71L protein required for dephosphorylation of translation initiation factor eIF2α and inhibiting activation of pro-apoptotic CHOP[J]. Virology, 2017, 504:107-113.
[49]	KOYAMA A H, ADACHI A, IRIE H. Physiological significance of apoptosis during animal virus infection[J]. Int Rev Immunol, 2003, 22(5-6):341-359.
[50]	ORVEDAHL A, ALEXANDER D, TALLÓCZY Z, et al. HSV-1 ICP34. 5 confers neurovirulence by targeting the Beclin 1 autophagy protein[J]. Cell Host Microbe, 2007, 1(1):23-35.
[51]	HERNAEZ B, CABEZAS M, MUNOZ-MORENO R, et al. A179L, a new viral Bcl2 homolog targeting Beclin 1 autophagy related protein[J]. Curr Mol Med, 2013, 13(2):305-316.
[52]	CHEN S, ZHANG X H, NIE Y, et al. African swine fever virus protein E199L promotes cell autophagy through the interaction of PYCR2[J]. Virol Sin, 2021, 36(2):196-206.
[53]	DREUX M, CHISARI F V. Viruses and the autophagy machinery[J]. Cell Cycle, 2010, 9(7):1295-1307.
[54]	SHIMMON G L, HUI J Y K, WILEMAN T E, et al. Autophagy impairment by African swine fever virus[J]. J Gen Virol, 2021, 102(8):001637.
[55]	RIVERA J, ABRAMS C, HERNAEZ B, et al. The MyD116 African swine fever virus homologue interacts with the catalytic subunit of protein phosphatase 1 and activates its phosphatase activity[J]. J Virol, 2007, 81(6):2923-2929.
[56]	LIU Q, HU W, ZHANG Y L, et al. Anti-viral immune response in the lung and thymus:Molecular characterization and expression analysis of immunoproteasome subunits LMP2, LMP7 and MECL-1 in pigs[J]. Biochem Biophys Res Commun, 2018, 502(4):472-478.
[57]	HURTADO C, GRANJA A G, BUSTOS M J, et al. The C-type lectin homologue gene (EP153R) of African swine fever virus inhibits apoptosis both in virus infection and in heterologous expression[J]. Virology, 2004, 326(1):160-170.
[58]	HURTADO C, BUSTOS M J, GRANJA A G, et al. The African swine fever virus lectin EP153R modulates the surface membrane expression of MHC class I antigens[J]. Arch Virol, 2011, 156(2):219-234.
[59]	JIA N, OU Y W, PEJSAK Z, et al. Roles of African swine fever virus structural proteins in viral infection[J]. J Vet Res, 2017, 61(2):135-143.
[60]	CHAULAGAIN S, DELHON G A, KHATIWADA S, et al. African swine fever virus CD2v protein induces β-interferon expression and apoptosis in swine peripheral blood mononuclear cells[J]. Viruses, 2021, 13(8):1480.
[61]	SUN W Q, ZHANG H, FAN W H, et al. Evaluation of cellular immunity with ASFV infection by swine leukocyte antigen (SLA)-peptide tetramers[J]. Viruses, 2021, 13(11):2264.
[62]	CHEN W Y, ZHAO D M, HE X J, et al. A seven-gene-deleted African swine fever virus is safe and effective as a live attenuated vaccine in pigs[J]. Sci China Life Sci, 2020, 63(5):623-634.
[63]	GALLARDO C, SOLER A, RODZE I, et al. Attenuated and non-haemadsorbing (non-HAD) genotype II African swine fever virus (ASFV) isolated in Europe, Latvia 2017[J]. Transbound Emerg Dis, 2019, 66(3):1399-1404.
[64]	GAVIER-WIDÉN D, STÅHL K, DIXON L. No hasty solutions for African swine fever[J]. Science, 2020, 367(6478):622-624.
[65]	YANG J N, TANG K C, CAO Z D, et al. Demand-driven spreading patterns of African swine fever in China[J]. Chaos, 2021, 31(6):061102.
[66]	SÁNCHEZ E G, PÉREZ-NU'ÑEZ D, REVILLA Y. Development of vaccines against African swine fever virus[J]. Virus Res, 2019, 265:150-155.