于家荣,王筱真,左媛媛,高晟斌,徐蛟,房琳琳,魏荣,包静月,王志亮

• 1:中国动物卫生与流行病学中心

摘要(Abstract)：

非洲猪瘟病毒（ASFV）是一种大型、复杂的DNA病毒，可感染家猪和野猪，对全球养猪业构成重大威胁。除越南外，目前尚未有针对该病的商品化疫苗。ASFV基因及其表达产物的免疫调节能力与病毒毒力和致病性密切相关。目前发现ASFV可通过多种策略来抑制被感染动物的先天性免疫反应。本文聚焦于ASFV相关蛋白与宿主防御的复杂机制，从干扰素信号调节、炎症信号通路调控以及细胞凋亡影响等几个方面进行系统总结，以期为ASFV疫苗和抗病毒药物的研发提供参考。

关键词(KeyWords)： 非洲猪瘟病毒;天然免疫;免疫逃逸;分子机制

Abstract:

Keywords:

基金项目(Foundation): “十四五”国家重点研发计划项目（2022YFD1800500）

作者(Author): 于家荣,王筱真,左媛媛,高晟斌,徐蛟,房琳琳,魏荣,包静月,王志亮

参考文献(References)：

• [1] DIXON L,SUN H,ROBERTS H. African swine fever[J].Antiviral research,2019,165:34-41.
• [2] MONTGOMERY R E. On a form of swine fever occurring in British East Africa(Kenya Colony)[J]. Journal of comparative pathology and therapeutics,1921,34:159-191.
• [3] TULMAN E,DELHON G A,KU B,et al. African swine fever virus[J]. Current topics in microbiology and immunology,2009,328(1):43-87.
• [4] PéREZ-Nú?EZ D,SUNWOO S Y,SáNCHEZ E G,et al. Evaluation of a viral DNA-protein immunization strategy against African swine fever in domestic pigs[J].Veterinary immunology and immunopathology,2019,208:34-43.
• [5] DIXON L K,CHAPMAN D A,NETHERTON C L,et al.African swine fever virus replication and genomics[J].Virus research,2013,173(1):3-14.
• [6] IYER L M,BALAJI S,KOONIN E V,et al. Evolutionary genomics of nucleo-cytoplasmic large DNA viruses[J].Virus research,2006,117(1):156-184.
• [7] ZHOU P,LI L F,ZHANG K,et al. Deletion of the H240R gene of African swine fever virus decreases infectious progeny virus production due to aberrant virion morphogenesis and enhances inflammatory cytokine expression in porcine macrophages[J]. Journal of virology,2022,96(3):e01667-01621.
• [8] CACKETT G,SYKORA M,WERNER F. Transcriptome view of a killer:African swine fever virus[J]. Biochemical society transactions,2020,48(4):1569-1581.
• [9] ALONSO C,BORCA M,DIXON L,et al. ICTV virus taxonomy profile:Asfarviridae[J]. Journal of general virology,2018,99(5):613-614.
• [10] ANDRéS G,GARCIA?-ESCUDERO R N,SALAS M A L,et al. Repression of African swine fever virus polyprotein pp220-encoding gene leads to the assembly of icosahedral core-less particles[J]. Journal of virology,2002,76(6):2654-2666.
• [11] REDREJO-RODRíGUEZ M,RODRíGUEZ J M,SUáREZ C,et al. Involvement of the reparative DNA polymerase Pol X of African swine fever virus in the maintenance of viral genome stability in vivo[J]. Journal of virology,2013,87(17):9780-9787.
• [12] HE W R,YUAN J,MA Y H,et al. Modulation of host antiviral innate immunity by African swine fever virus:a review[J]. Animals,2022,12(21):2935.
• [13] WANG N,ZHAO D,WANG J,et al. Architecture of African swine fever virus and implications for viral assembly[J]. Science,2019,366(6465):640-644.
• [14] SUN H,YANG J,ZHANG Z,et al. The African swine fever virus gene MGF_360-4L inhibits interferon signaling by recruiting mitochondrial selective autophagy receptor SQSTM1 degrading MDA5 antagonizing innate immune responses[J]. mBio,2025,16(4):e02677-02624.
• [15] CORREIA S,VENTURA S,PARKHOUSE R M.Identification and utility of innate immune system evasion mechanisms of ASFV[J]. Virus research,2013,173(1):87-100.
• [16] LIU X,CHEN H,YE G,et al. African swine fever virus pB318L,a trans-geranylgeranyl-diphosphate synthase,negatively regulates cGAS-STING and IFNAR-JAKSTAT signaling pathways[J]. PLoS Pathogens,2024,20(4):e1012136.
• [17] RAZZUOLI E,FRANZONI G,CARTA T,et al.Modulation of type I interferon system by African swine fever virus[J]. Pathogens,2020,9(5):361.
• [18] LI M,LIU X,PENG D,et al. The I7L protein of African swine fever virus is involved in viral pathogenicity by antagonizing the IFN-γ-triggered JAK-STAT signaling pathway through inhibiting the phosphorylation of STAT1[J]. PLoS Pathogens,2024,20(9):e1012576.
• [19] 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]. The journal of immunology,2006,176(1):451-462.
• [20] 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.
• [21] GALINDO BARREALES I,HERNAEZ B,DíAZ-GIL G,et al. A179L,a viral Bcl-2 homologue, targets the core Bcl-2 apoptotic machinery and its upstream BH3activators with selective binding restrictions for Bid and Noxa[J]. Virology,2008,375(2):561-572.
• [22] 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.
• [23] 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.
• [24] LIU H,GUO Y,GUO Z,et al. Integration of CRISPR screening and proteomic analysis of WDR91 manipulation of endosome-to-cytosol transport of African swine fever virus[J/OL]. Science China life sciences,2025:1-4[2025-02-13]. https：//doi.org/10.1007/s11427-024-2739-9.
• [25] BANJARA S,SHIMMON G L,DIXON L K,et al.Crystal structure of African swine fever virus A179L with the autophagy regulator Beclin[J]. Viruses,2019,11(9):789.
• [26] ZHU Y,DENG J,NAN M L,et al. The interplay between pattern recognition receptors and autophagy in inflammation,advances in experimental medicine and biology[J/OL]. Autophagy regulation of innate immunity,2019:79-108[2019-11-15]. https：//doi.org/10.1007/978-981-15-0606-2_6.
• [27] GARCíA-BELMONTE R,PéREZ-Nú?EZ D,PITTAU M,et al. African swine fever virus Armenia/07 virulent strain controls interferon beta production through the cGAS-STING pathway[J]. Journal of virology,2019,93(12):e02298-18.
• [28] DIXON L K,CHAPMAN D A G,NETHERTON C L,et al.African swine fever virus replication and genomics[J].Virus research,2013,173(1):3-14.
• [29] O'DONNELL V,HOLINKA L G,GLADUE D P,et al.African swine fever virus Georgia isolate harboring deletions of MGF360 and MGF505 genes is attenuated in swine and confers protection against challenge with virulent parental virus[J]. Journal of virology,2015,221:8-14.
• [30] AFONSO C L,PICCONE M E,ZAFFUTO K M,et al.African swine fever virus multigene family 360 and530 genes affect host interferon response[J]. Journal of virology,2004,78(4):1858-1864.
• [31] CORREIA S,VENTURA S,PARKHOUSE R M.Identification and utility of innate immune system evasion mechanisms of ASFV[J]. Virus research,2013,173(1):87-100.
• [32] ZHANG K,YANG B,SHEN C,et al. MGF360-9L is a major virulence factor associated with the African swine fever virus by antagonizing the JAK/STAT signaling pathway[J]. mBio,2022,14(4):e02330-21.
• [33] YANG K,XUE Y,NIU H,et al. African swine fever virus MGF360-11L negatively regulates cGAS-STINGmediated inhibition of type I interferon production[J].Veterinary research,2022,53(1):1-12.
• [34] ZHUO Y,GUO Z,BA 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]. Virologica sinica,2021,36(2):176-186.
• [35] WANG Y,CUI S,XIN T,et al. African swine fever virus MGF360-14L negatively regulates type I interferon signaling by targeting IRF3[J]. Frontiers in cellular and infection microbiology,2022,11:e818969.
• [36] LI D,YANG W,LI L,et al. African swine fever virus MGF-505-7R negatively regulates cGAS-STING-mediated signaling pathway[J]. The journal of immunology,2021,206(8):1844-1857.
• [37] LI D,ZHANG J,YANG W,et al. African swine fever virus protein MGF-505-7R promotes virulence and pathogenesis by inhibiting JAK1-and JAK2-mediated signaling[J]. Journal of biological chemistry,2021,297(5):101190.
• [38] YANG K,HUANG Q,WANG R,et al. African swine fever virus MGF505-11R inhibits type I interferon production by negatively regulating the cGAS-STINGmediated signaling pathway[J]. Veterinary microbiology,2021,263:109-265.
• [39] LUKHELE S,BOUKHALED G M,BROOKS D G. Type I interferon signaling,regulation and gene stimulation in chronic virus infection[J]. Seminars in immunology,2019,43:101277.
• [40] PLATANIAS L C. Mechanisms of type-I-and typeII-interferon-mediated signalling[J]. Nature reviews immunology,2005,5(5):375-386.
• [41] HONG J,CHI X,YUAN X,et al. I226R Protein of African swine fever virus is a suppressor of innate antiviral responses[J]. Virology,2012,575(1):160-170.
• [42] ZHU Z,LI S,MA C,et al. African swine fever virus E184L protein interacts with innate immune adaptor STING to block IFN production for viral replication and pathogenesis[J]. The journal of immunology,2023,210(4):442-458.
• [43] YE G,LIU H,LIU X,et al. African swine fever virus H240R protein inhibits the production of type I interferon through disrupting the oligomerization of STING[J].Journal of virology,2023,97(9):16.
• [44] LIU H,ZHU Z,FENG T,et al. African swine fever virus E120R protein inhibits interferon beta production by interacting with IRF3 to block its activation[J]. Journal of virology,2021,95(18):21-24.
• [45] HUANG L,XU W,LIU H,et al. African swine fever virus pI215L negatively regulates cGAS-STING signaling pathway through recruiting RNF138 to inhibit K63-linked ubiquitination of TBK1[J]. The journal of immunology,2021,207(11):2754-2769.
• [46] BORCA M V,KUTISH G F,AFONSO C L,et al.An African swine fever virus gene with similarity to the T-lymphocyte surface antigen CD2 mediates hemadsorption[J]. Virology,1994,199(2):463-468.
• [47] LI Y H,PENG J L,XU Z S,et al. African swine fever virus cysteine protease pS273R inhibits type I interferon signaling by mediating STAT2 degradation[J]. Journal of virology,2023,97(3):e00123-23.
• [48] HENRIQUES E S,BRITO R M M,SOARES H,et al.Modeling of the toll-like receptor 3 and a putative toll-like receptor 3 antagonist encoded by the African swine fever virus[J]. Protein science,2011,20(2):247-255.
• [49] 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]. Archives of virology,2011,156(4):597-609.
• [50] RAN Y,LI D,XIONG M-G,et al. African swine fever virus I267L acts as an important virulence factor by inhibiting RNA polymerase III-RIG-I-mediated innate immunity[J]. PLoS Pathogens,2022,18:e1010270.
• [51] BORCA M V,RAMIREZ-MEDINA E,SILVA E,et al.ASF vaccine candidate ASFV-G-ΔI177L does not exhibit residual virulence in long-term clinical studies[J].Pathogens,2023,12(6):805.
• [52] RIVERA J,ABRAMS C,HERNAE?Z 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]. Journal of virology,2007,81(6):2923-2929.
• [53] ZHANG F,HOPWOOD P,ABRAMS C C,et al.Macrophage transcriptional responses following in vitro infection with a highly virulent African swine fever virus isolate[J]. Journal of virology,2006,80(21):10514-10521.
• [54]翁长江.非洲猪瘟病毒免疫调节基因的功能及其在病毒感染和致病中的作用[J].中国兽医杂志，2023,59(11):74-84.
• [55] GIL S,SEPúLVEDA N,ALBINA E,et al. The lowvirulent African swine fever virus(ASFV/NH/P68)induces enhanced expression and production of relevant regulatory cytokines(IFNα,TNFα and IL12p40)on porcine macrophages in comparison to the highly virulent ASFV/L60[J]. Archives of virology,2008,153(10):1845-1854.
• [56] FISHBOURNE E,ABRAMS C C,TAKAMATSU H-H,et al. Modulation of chemokine and chemokine receptor expression following infection of porcine macrophages with African swine fever virus[J]. Veterinary microbiology,2013,162(2/3/4):937-943.
• [57] REVILLA Y,CALLEJO M,RODRIG?UEZ J M,et al.Inhibition of nuclear factorκB activation by a virusencoded IκB-like protein[J]. Journal of biological chemistry,1998,273(9):5405-5411.
• [58] YANG J,LI S,FENG T,et al. African swine fever virus F317L protein inhibits NF-κB activation to evade host immune response and promote viral replication[J].mSphere,2021,6(5):e00658-21.
• [59] 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]. Journal of virology,2000,74(20):9412-9420.
• [60] 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]. Journal of biological chemistry,2004,279(51):53736-53746.
• [61] CHEN X,LI L F,YANG Z Y,et al. The African swine fever virus I10L protein inhibits the NF-B signaling pathway by targeting IKK[J]. Journal of virology,2023:97(9):21.
• [62] LI J,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 Pathogens,2021(7):e1009733.
• [63] ZHAO G,LI T,LIU X,et al. African swine fever virus cysteine protease pS273R inhibits pyroptosis by noncanonically cleaving gasdermin D[J]. Journal of biological chemistry,2022,298(1):101480.
• [64] CHEN Y,LIN J S. The application of aptamer in apoptosis[J]. Biochimie,2017,132:1-8.
• [65] FAN L. Signaling pathways involved in regulating apoptosis induction in host cells upon PRRSV infection[J].Virus genes,2019,55(4):433-439.
• [66] HERNáEZ B,DIA?Z-GIL G,GARCIA?-GALLO M,et al.The African swine fever virus dynein-binding protein p54induces infected cell apoptosis[J]. FEBS letters,2004,569(1/2/3):224-228.
• [67] LI J,JIN P,ZHU J,et al. Multi-scale GCN-assisted twostage network for joint segmentation of retinal layers and discs in peripapillary OCT images[J]. Biomedical optics express,2021,12:2204-2220.
• [68] BANJARA S,CARIA S,DIXON L K,et al. Structural insight into African swine fever virus A179L-mediated inhibition of apoptosis[J]. Journal of virology,2017,75(6):2535-2543.
• [69] GALINDO I,HERNAEZ B,DíAZ-GIL G,et al. A179L,a viral Bcl-2 homologue,targets the core Bcl-2 apoptotic machinery and its upstream BH3 activators with selective binding restrictions for Bid and Noxa[J]. Virology,2008,375(2):561-572.
• [70] NEILAN J G,LU Z,KUTISH G F,et al. A BIR motif containing gene of African swine fever virus,4CL,is nonessential for growthin vitroand viral virulence[J].Virology,1997,230(2):252-264.
• [71] NOGAL M A L,GONZAL?EZ DE BUITRAGO G,RODR?G?UEZ C,et al. African swine fever virus IAP homologue inhibits caspase activation and promotes cell survival in mammalian cells[J]. Journal of virology,2001,75(6):2535-2543.
• [72] RODRIG?UEZ C I,NOGAL M A L,CARRASCOSA A L,et al. African swine fever virus IAP-like protein induces the activation of nuclear factor kappa B[J]. Journal of virology,2002,76(8):3936-3942.
• [73] HURTADO C,GRANJA A G,BUSTOS M A 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.
• [74] ZHANG F,MOON A,CHILDS K,et al. The African swine fever virus DP71L protein recruits the protein phosphatase 1 catalytic subunit to dephosphorylate eIF2αand inhibits CHOP induction but is dispensable for these activities during virus infection[J]. Journal of virology,2010,84(20):10681-10689.
• [75] BANJARA S,SHIMMON G,DIXON L,et al. Crystal structure of African swine fever virus A179L with the autophagy regulator Beclin[J]. Viruses,2019,11(9):789.
• [76] HERNAEZ B,CABEZAS M,MUNOZ-MORENO R,et al.A179L,a new viral Bcl2 homolog targeting Beclin 1autophagy related protein[J]. Current molecular medicine,2013,13(2):305-316.
• [77] CHEN S,ZHANG X,NIE Y,et al. African swine fever virus protein E199L promotes cell autophagy through the interaction of PYCR2[J]. Virologica sinica,2021,36(2):196-206.
• [78] HU B,ZHONG G,DING S,et al. African swine fever virus protein p17 promotes mitophagy by facilitating the interaction of SQSTM1 with TOMM70[J]. Virulence,2023,14(1):2232707.
• [79] SUN M,YU S,GE H,et al. The A137R protein of African swine fever virus inhibits type I interferon production via the autophagy-mediated lysosomal degradation of TBK1[J]. Journal of virology,2022,96(9):e01957-21.
• [80] MONTEAGUDO P L,LACASTA A,LóPEZ E,et al.BA71ΔCD2:a new recombinant live attenuated African swine fever virus with cross-protective capabilities[J].Journal of virology,2017,91(21):e01058-17.
• [81] CHENG M,KANYEMA M M,SUN Y,et al. African swine fever virus L83L negatively regulates the cGASSTING-mediated IFN-I pathway by recruiting tollip to promote STING autophagic degradation[J]. Journal of virology,2023,97(3):e01923-22.
• [82] YE G,ZHANG Z,LIU X,et al. African swine fever virus pH240R enhances viral replication via inhibition of the type I IFN signaling pathway[J]. Journal of virology,2024,98(3):e01834-01823.
• [83] ZHAO X,ZHANG Y,JIA H,et al. Diversities of African swine fever virus host-virus dynamics revealed by singlecell profiling[J]. Journal of virology,2025,99(3):e02035-02024.
• [84] LIU W,LI H,LIU B,et al. A new vaccination regimen using adenovirus-vectored vaccine confers effective protection against African swine fever virus in swine[J].Emerging microbes&infections,2023,12(2):2233643.