猪德尔塔冠状病毒感染与抗感染研究进展

doi:10.16431/j.cnki.1671-7236.2025.03.030

摘要/Abstract

摘要： 猪德尔塔冠状病毒(Porcine deltacoronavirus,PDCoV)是一种新型肠道冠状病毒，主要感染哺乳仔猪，临床表现为腹泻、呕吐、脱水等症状，发病率可达100%。PDCoV严重危害新生仔猪健康，现已成为引起猪群腹泻的主要病原体之一。PDCoV通过膜融合及受体介导的内吞作用侵入宿主细胞，S蛋白是病毒侵入细胞的主要结构，表面氨基肽酶N、小窝蛋白是病毒侵入细胞的关键位点。此外，表面氨基肽酶N目前被认为是PDCoV跨物种传播的重要位点。细胞通过干扰素(IFN)基因表达、胆固醇代谢及N蛋白泛素化等途径引发抗感染。PDCoV通过自身结构蛋白、辅助蛋白及非结构蛋白等通过干扰IFN的表达及诱导侵染细胞凋亡等途径产生免疫逃避，进而持续侵染宿主细胞。目前用于预防和控制PDCoV感染的商业疫苗或抗病毒药物多在试验研发阶段或初上市阶段，其对PDCoV的预防和控制的临床效果亟需市场验证。尤其是针对病毒复制、免疫逃逸、抗PDCoV宿主因子等靶点开发的抗病毒药物或疫苗，为未来开发新型疫苗或抗病毒药物研发提供了新的研究方向和坚实的基础。笔者通过阐述PDCoV与宿主之间的感染和抗感染机制，探究多种抗病毒药物抑制PDCoV感染的潜在作用机制，为研究PDCoV致病机制、抗PDCoV感染治疗以及新药物的开发提供参考。

关键词: 猪德尔塔冠状病毒(PDCoV); 致病性; 免疫逃逸; 抗病毒机制

Abstract: Porcine deltacoronavirus (PDCoV),a novel enteric coronavirus,primarily infects suckling piglets,causing clinical symptoms such as diarrhea,vomiting and dehydration with a morbidity rate of up to 100%.PDCoV poses a significant threat to the health of newborn piglets and has become one of the primary pathogens causing diarrhea in swine.PDCoV enters host cells through membrane fusion and receptor-mediated endocytosis,with the S protein being the major structural protein for cell entry.Aminopeptidase N and caveolin on the cell surface have been identified as critical entry sites.Additionally,aminopeptidase N is currently considered a crucial determinant of PDCoV cross-species transmission.Host cells initiate an antiviral response through the expression of interferon (IFN) genes,cholesterol metabolism,and N protein ubiquitination.PDCoV evades the host immune response by interfering with IFN expression and inducing apoptosis of infected cells through its structural,accessory and non-structural proteins.Commercial vaccines or antiviral drugs for the prevention and control of PDCoV infection are currently in the experimental or early market stages,their clinical efficacy in preventing and controlling PDCoV infection still requires market validation.In particular,the development of antiviral drugs or vaccines targeting viral replication,immune evasion,and host factors against PDCoV provides new research directions and a solid foundation for the development of novel vaccines or antiviral drugs.By elucidating the infection and anti-infection mechanisms between PDCoV and the host,and investigating the potential mechanisms of various antiviral drugs in inhibiting PDCoV infection,this review provides a reference for studying the pathogenesis of PDCoV,antiviral therapy and the development of new drugs.

Key words: Porcine deltacoronavirus (PDCoV); pathogenicity; immune escape; antiviral mechanism

中图分类号:

S852.65⁺1

毛福超, 翟崇凯, 田文静, 王聪慧, 宋敏杰, 王迎鲜, 张贺伟. 猪德尔塔冠状病毒感染与抗感染研究进展[J]. 中国畜牧兽医, 2025, 52(3): 1281-1291.

MAO Fuchao, ZHAI Chongkai, TIAN Wenjing, WANG Conghui, SONG Minjie, WANG Yingxian, ZHANG Hewei. An Updated Review of Porcine Deltacoronavirus in Terms of Infection and Anti-infection Research[J]. China Animal Husbandry and Veterinary Medicine, 2025, 52(3): 1281-1291.

参考文献

[1] ZHANG S,ZHANG S S,HOU Y C,et al.Porcine deltacoronavirus infection disrupts the intestinal mucosal barrier and inhibits intestinal stem cell differentiation to goblet cells via the Notch signaling pathway[J].Journal of Virology,2023,97(6):e0068923.
[2] TURLEWICZ-PODBIELSKA H,POMORSKA-MÓL M.Porcine coronaviruses:Overview of the state of the art[J].Virologica Sinica,2021,36(5):833-851.
[3] LIU Y,WANG B,LIANG Q Z,et al.Roles of two major domains of the Porcine deltacoronavirus S1 subunit in receptor binding and neutralization[J].Journal of Virology,2021,95(24):e01118-21.
[4] XIA S J,XIAO W W,ZHU X R,et al.Porcine deltacoronavirus resists antibody neutralization through cell-to-cell transmission[J].Emerging Microbes & Infections,2023,12(1):2207688.
[5] KONG F Z,WANG Q H,KENNEY S P,et al.Porcine deltacoronaviruses:Origin,evolution,cross-species transmission and zoonotic potential[J].Pathogens,2022,11(1):79.
[6] ZHANG B T,ZHAO S Q,ZHONG C Y,et al.Comparison of pathogenicity of Porcine deltacoronavirus CZ2020 from cell culture and intestinal contents in 27-day-old piglets[J].Microbial Pathogenesis,2022,170:105723.
[7] LI J Z,ZHAO S Q,ZHANG B T,et al.A novel recombinant S-based subunit vaccine induces protective immunity against Porcine deltacoronavirus challenge in piglets[J].Journal of Virology,2023,97(11):e0095823.
[8] TANG P,CUI E,SONG Y,et al.Porcine deltacoronavirus and its prevalence in China:A review of epidemiology,evolution,and vaccine development[J].Archives of Virology,2021,166(11):2975-2988.
[9] ZHAI S L,WEI W K,LI X P,et al.Occurrence and sequence analysis of Porcine deltacoronaviruses in Southern China[J].Virology Journal,2016,13(1):136.
[10] HE W T,JI X,HE W,et al.Genomic epidemiology,evolution,and transmission dynamics of Porcine deltacoronavirus[J].Molecular Biology Evolution,2020,37(9):2641-2654.
[11] JI W,PENG Q,FANG X,et al.Structures of a Deltacoronavirus spike protein bound to porcine and human receptors[J].Nature Communications,2022,13(1):1467.
[12] LEDNICKY J A,TAGLIAMONTE M S,WHITE S K,et al.Independent infections of Porcine deltacoronavirus among Haitian children[J].Nature,2021,600(7887):133-137.
[13] SHANG J,ZHENG Y,YANG Y,et al.Cryo-electron microscopy structure of Porcine deltacoronavirus spike protein in the prefusion state[J].Journal of Virology,2018,92(4):e01556-17.
[14] ZHANG J L,CHEN J F,SHI D,et al.Porcine deltacoronavirus enters cells via two pathways:A protease-mediated one at the cell surface and another facilitated by cathepsins in the endosome[J].Journal of Biological Chemistry,2019,294(25):9830-9843.
[15] CHEN R,FU J Y,HU J F,et al.Identification of the immunodominant neutralizing regions in the spike glycoprotein of Porcine deltacoronavirus[J].Virus Research,2020,276:197834.
[16] LI S Q,XIAO D,ZHAO L W,et al.Porcine deltacoronavirus (PDCoV) entry into PK-15 cells by caveolae-mediated endocytosis[J].Viruses,2022,14(3):496.
[17] BARMAN S,NAYAK D P.Lipid raft disruption by cholesterol depletion enhances Influenza A virus budding from MDCK cells[J].Journal of Virology,2007,81(22):12169-12178.
[18] JEON J H,LEE C.Cholesterol is important for the entry process of Porcine deltacoronavirus[J].Archives of Virology,2018,163(11):3119-3124.
[19] STENCEL-BAERENALD J E,REISS K,REITER D M,et al.The sweet spot:Defining virus-sialic acid interactions[J].Nature Reviews Microbiology,2014,12(11):739-749.
[20] YUAN Y X,ZU S P,ZHANG Y F,et al.Porcine deltacoronavirus utilizes sialic acid as an attachment receptor and trypsin can influence the binding activity[J].Viruses,2021,13(12):2442.
[21] DUAN C.An updated review of Porcine deltacoronavirus in terms of prevalence,pathogenicity,pathogenesis and antiviral strategy[J].Frontiers in Veterinary Science,2022,8:811187.
[22] JUNG K,VASQUEZ-LEE M,SAIF L J.Replicative capacity of Porcine deltacoronavirus and Porcine epidemic diarrhea virus in primary bovine mesenchymal cells[J].Veterinary Microbiology,2020,244:108660.
[23] GIMENEZ-LIROLA L G,ZHANG J,CARRILLO-AVILA J A,et al.Reactivity of Porcine epidemic diarrhea virus structural proteins to antibodies against Porcine enteric coronaviruses:Diagnostic implications[J].Journal of Clinical Microbiology,2017,55(5):1426-1436.
[24] JUNG K,HU H,SAIF L J.Calves are susceptible to infection with the newly emerged Porcine deltacoronavirus,but not with the Swine enteric alphacoronavirus,Porcine epidemic diarrhea virus[J]. Archives of Virology,2017,162(8):2357-2362.
[25] IBORRA S,SANCHO D.Signalling versatility following self and non-self sensing by myeloid C-type lectin receptors[J].Immunobiology,2015,220(2):175-184.
[26] XU Z C,ZHONG Z L,HUANG S J,et al.Porcine deltacoronavirus induces TLR3,IL-12,IFN-alpha,IFN-beta and PKR mRNA expression in infected Peyer’s patches in vivo[J].Veterinary Microbiology,2019,228:226-233.
[27] KE W T,WU X L,FANG P X,et al.Cholesterol 25-hydroxylase suppresses Porcine deltacoronavirus infection by inhibiting viral entry[J].Virus Research,2021,295:198306.
[28] JIAO Y J,KONG N,WANG H,et al.PABPC4 broadly inhibits Coronavirus replication by degrading nucleocapsid protein through selective autophagy[J].Microbiology Spectrum,2021,9(2):e00908-21.
[29] CHEN J,FANG P X,WANG M H,et al.Porcine deltacoronavirus nucleocapsid protein antagonizes IFN-β production by impairing dsRNA and PACT binding to RIG-Ⅰ[J].Virus Genes,2019,55(4):520-531.
[30] DING Z,LUO S,GONG W,et al.Subcellular localization of the Porcine deltacoronavirus nucleocapsid protein[J].Virus Genes,2020,56(6):687-695.
[31] LUO J Y,FANG L R,DONG N,et al.Porcine deltacoronavirus (PDCoV) infection suppresses RIG-Ⅰ-mediated interferon-β production[J].Virology,2016,495:10-17.
[32] JI L K,LI S S,ZHU W X,et al.Porcine deltacoronavirus nucleocapsid protein suppressed IFN-β production by interfering porcine RIG-Ⅰ dsRNA-Binding and K63-linked polyubiquitination[J].Frontiers in Immunology,2019,10:1024.
[33] JI L K,WANG N,MA J J,et al.Porcine deltacoronavirus nucleocapsid protein species-specifically suppressed IRF7-induced type Ⅰ interferon production via ubiquitin-proteasomal degradation pathway[J].Veterinary Microbiology,2020,250:108853.
[34] ZHAO Y J,YUAN J L,XIAO D,et al.HSP90AB1 is a host factor that promotes Porcine deltacoronavirus replication[J].Journal of Biological Chemistry,2024,300(1):105536.
[35] QIN P,LUO W T,SU Q,et al.The Porcine deltacoronavirus accessory protein NS6 is expressed in vivo and incorporated into virions[J].Virology,2021,556:1-8.
[36] FANG P X,ZHANG H C,CHENG T,et al.Porcine deltacoronavirus accessory protein NS6 harnesses VPS35-mediated retrograde trafficking to facilitate efficient viral infection[J].Journal of Virology,2023,97(10):e0095723.
[37] LIU Q,WANG H Y.Porcine enteric coronaviruses:An updated overview of the pathogenesis,prevalence,and diagnosis[J].Veterinary Research Communications,2021,45(2-3):75-86.
[38] FANG P X,FANG L R,REN J,et al.Porcine deltacoronavirus accessory protein NS6 antagonizes interferon beta production by interfering with the binding of RIG-Ⅰ/MDA5 to double-stranded RNA [J].Journal of Virology,2018,92(15):e00712-18.
[39] MOU C H,XIE S H,ZHU L Q,et al.Porcine deltacoronavirus NS7a antagonizes JAK/STAT pathway by inhibiting the interferon-stimulated gene factor 3(ISGF3) formation[J].International Journal of Biological Macromolecules,2024,264:130693.
[40] ZHU X Y,FANG L R,WANG D,et al.Porcine deltacoronavirus NSP5 inhibits interferon-beta production through the cleavage of NEMO[J].Virology,2017,502:33-38.
[41] WU Y,LI M W,TIAN J,et al.Broad antagonism of Coronaviruses nsp5 to evade the host antiviral responses by cleaving POLDIP3[J].PLoS Pathogens,2023,19(10):e1011702.
[42] HUANG H X,LEI X X,ZHAO C C,et al.Porcine deltacoronavirus nsp5 antagonizes type Ⅰ interferon signaling by cleaving IFIT3[J].Journal of Virology,2024,98(2):e0168223.
[43] FANG P X,HONG Y Y,XIA S J,et al.Porcine deltacoronavirus NSP10 antagonizes interferon-β production independently of its zinc finger domains[J].Virology,2021,559:46-56.
[44] LIU X R,FANG P X,FANG L R,et al.Porcine deltacoronavirus NSP15 antagonizes interferon-β production independently of its endoribonuclease activity[J].Molecular Immunology,2019,114:100-107.
[45] XU Z C,ZHANG Y,CAO Y C.The roles of apoptosis in swine response to viral infection and pathogenesis of Swine enteropathogenic coronaviruses[J].Frontiers in Veterinary Science,2020,7:572425.
[46] JIN L Y,CHANGHEE L.Porcine deltacoronavirus induces caspase-dependent apoptosis through activation of the cytochrome c-mediated intrinsic mitochondrial pathway[J].Virus Research,2018,253:112-123.
[47] LUO Y Y,FEI L,YUE H,et al.Prevalence and genomic characteristics of a novel reassortment mammalian Orthoreovirus type 2 in diarrhea piglets in Sichuan,China[J].Infection Genetics and Evolution,2020,85:104420.
[48] DUAN C,LIU Y,HAO Z H,et al.Ergosterol peroxide suppresses Porcine deltacoronavirus (PDCoV)-induced autophagy to inhibit virus replication via p38 signaling pathway[J].Veterinary Microbiology,2021,257:109068.
[49] TANG R F,GUO L J,FAN Q J,et al.Porcine deltacoronavirus infection is inhibited by Griffithsin in cell culture[J].Veterinary Microbiology,2022,264:109299.
[50] BROWN A J,WON J J,GRAHAM R L,et al.Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic Deltacoronaviruses with a highly divergent RNA dependent RNA polymerase[J].Antiviral Research,2019,169:104541.
[51] LI M X,ZHANG L P,PAN L,et al.Nicotinamide efficiently suppresses Porcine epidemic diarrhea virus and Porcine deltacoronavirus replication[J].Viruses,2023,15(7):1591.
[52] YANG Y Q,CAO L,GAO H Y,et al.Discovery,optimization and target identification of novel potent broad-spectrum antiviral inhibitors[J].Journal of Medicinal Chemistry,2019,62(8):4056-4073.
[53] ZHAI X F,WANG S L,ZHU M Y,et al.Antiviral effect of lithium chloride and diammonium glycyrrhizinate on Porcine deltacoronavirus in vitro[J].Pathogens,2019,8(3):144.
[54] BAI D C,FANG L R,XIA S J,et al.Porcine deltacoronavirus (PDCoV) modulates calcium influx to favor viral replication[J].Virology,2020,539(1):38-48.
[55] DUAN C,WANG J C,LIU Y,et al.Antiviral effects of ergosterol peroxide in a pig model of Porcine deltacoronavirus (PDCoV) infection involves modulation of apoptosis and tight junction in the small intestine[J].Veterinary Research,2021,52(1):86.
[56] KONG F Z,NIU X Y,LIU M D,et al.Bile acids LCA and CDCA inhibited Porcine deltacoronavirus replication in vitro[J].Veterinary Microbiology,2021,257:109097.
[57] REN Z H,DING T,HE H Y,et al.Mechanism of selenomethionine inhibiting of PDCoV replication in LLC-PK1 cells based on STAT3/miR-125b-5p-1/HK2 signaling[J].Frontier in Immunology,2022,13:952852.
[58] SUN K,ZHANG Z M,XING J N,et al.Synthesis and pharmacodynamic evaluation of dihydropteridone derivatives against PDCoV in vivo and in vitro[J].Bioorganic Chemistry,2024,146:107322.
[59] SHI C X,LIANG W W,GUO M,et al.Chlorogenic acid inhibits Porcine deltacoronavirus release by targeting apoptosis[J].International Immunopharmacology,2024,127:111359.
[60] SUN Y M,LIU Z Z,SHEN S Y,et al.Inhibition of Porcine deltacoronavirus entry and replication by cepharanthine[J].Virus Research,2024,340:199303.
[61] JIANG Y H,ZHANG G Q,LI L T,et al.A novel host restriction factor MRPS6 mediates the inhibition of PDCoV infection in HIEC-6 cells[J].Frontier in Immunology,2024,15:1381026.
[62] MA N N,ZHANG M J,ZHOU J R,et al.Genome-wide CRISPR/Cas9 library screen identifies C16orf62 as a host dependency factor for Porcine deltacoronavirus infection[J].Emerging Microbes & Infections,2024,2:2400559.