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      牛病毒性腹瀉病毒生物型的遺傳基礎(chǔ)

      2017-04-11 07:43:59孟慶森劉芳芳孟相秋師新川趙建增
      生物技術(shù)通訊 2017年3期
      關(guān)鍵詞:毒株基因組編碼

      孟慶森,劉芳芳,孟相秋,師新川,趙建增,

      1.華威特(江蘇)生物制藥有限公司,江蘇 泰州 225300;

      2.華威特(北京)生物科技有限公司,北京 100085

      牛病毒性腹瀉病毒生物型的遺傳基礎(chǔ)

      孟慶森1,劉芳芳1,孟相秋2,師新川1,趙建增1,2

      1.華威特(江蘇)生物制藥有限公司,江蘇 泰州 225300;

      2.華威特(北京)生物科技有限公司,北京 100085

      牛病毒性腹瀉病毒(BVDV)是黃病毒科、瘟病毒屬成員,主要引起牛免疫抑制、腹瀉及繁殖障礙,是影響全球養(yǎng)牛業(yè)的重要致病原。根據(jù)BVDV在體內(nèi)對細(xì)胞的致病性,目前普遍將其分為2種生物型。不同生物型的基因結(jié)構(gòu)及分子致病學(xué)機(jī)制明顯不同,病毒基因變異可能產(chǎn)生新的生物型致病。我們簡要綜述BVDV生物型與基因結(jié)構(gòu)及疾病發(fā)生之間的關(guān)系。

      牛病毒性腹瀉病毒;生物型;基因變異

      牛病毒性腹瀉病毒(bovine viral diarrhea virus,BVDV)是黃病毒科、瘟病毒屬成員,是全球奶牛和肉牛群的重要致病原。該病毒還能感染豬、羊、鹿、駱駝及其他多種野生動物,引起高熱、白細(xì)胞減少、精神沉郁、腹瀉、免疫抑制、母畜繁殖障礙及產(chǎn)奶能力下降等疾病。由于在流行或感染過程中基因變異,BVDV有多種基因型及生物型,其致病機(jī)制呈復(fù)雜化,因而需要對其生物學(xué)特性進(jìn)行更深入的研究。

      BVDV病毒粒子由脂質(zhì)雙層膜包裹基因組RNA形成。外膜中插有病毒編碼的糖蛋白,后者攜帶病毒的主要抗原決定位點、受體結(jié)合位點及與細(xì)胞融合的位點[1]。病毒基因為單股正鏈RNA,長約12.5 kb[2],不同毒株基因長度可因缺失、插入及重復(fù)而變化。病毒可感染多種細(xì)胞,如牛腎細(xì)胞、牛睪丸細(xì)胞、牛肺細(xì)胞、胎羊睪丸細(xì)胞、豬腎細(xì)胞等。大多數(shù)學(xué)者認(rèn)為BVDV沒有血凝性,但也曾有某些毒株能夠凝集恒河猴、豬、綿羊和雛雞紅細(xì)胞的報道。

      1 BVDV基因結(jié)構(gòu)及基因分型

      病毒粒子含有一個大的開放讀框(ORF),由5'非翻譯區(qū)(5'UTR)、ORF編碼區(qū)、3'UTR組成[9]。致細(xì)胞突變型(CP型)BVDV的RNA基因組含12 573個堿基,ORF編碼3988個氨基酸殘基,相對分子質(zhì)量約449×103[3]。新的研究發(fā)現(xiàn),BVDV基因組長度差異較大,個別毒株的基因組長達(dá)15.5 kb。一株CP型毒株(U86599)蛋白可多達(dá)4983個氨基酸殘基,預(yù)測相對分子質(zhì)量達(dá)到558×103。

      各毒株間的5'UTR序列有較高的保守性,BVDV的3'非編碼區(qū)(3'NCR)始于ORF的終止密碼子TGA,由223~230個核苷酸組成,含有60 bp富含AT的序列,有一個8核苷酸重復(fù)序列(TGTATATA),無poly(A)尾結(jié)構(gòu)。3'NCR及5'UTR參與病毒復(fù)制和調(diào)控。ORF編碼一個前體多聚蛋白,后者經(jīng)細(xì)胞和病毒基因編碼的蛋白酶在翻譯的同時或翻譯后加工,裂解產(chǎn)生12種多肽,據(jù)其基因編碼序列,依次為5'-Npro-C-E0-E1-E2-P7-NS2-NS3-NS4A-NS4B-NS5A-NS5B。其中C、E0、E1、E2為結(jié)構(gòu)蛋白,其余為非結(jié)構(gòu)蛋白。利用免疫沉淀技術(shù),從感染BVDV的細(xì)胞內(nèi)可檢出相對分子質(zhì)量分別為220×103、165×103、118×103、84× 103、66×103、58×103、55×103、53×103、45×103、37×103和31×103共11種多肽,其中165×103、118×103、84× 103、66×103、58×103、55×103、53×103、45×103和31× 103蛋白處于糖基化狀態(tài)[4]。P7是位于E2蛋白下游的一個小肽,分子很小,不易檢測到,主要參與E2的功能調(diào)節(jié)。

      BVDV通常根據(jù)5'UTR、N(pro)和E2區(qū)的序列進(jìn)行分型。據(jù) 5'UTR將其分為 BVDV1和 BVDV2共2個基因型[5]。來自南美和北美的一些BVDV2株與歐洲、亞洲的BVDV2的5'UTR序列相似性為81.7%,其NS2/3編碼區(qū)6670~7186堿基也有相似的區(qū)別??蓪VDV2分為2a和2b基因亞型[6]。BVDV1a和BVDV1b的主要差異也位于這些區(qū)域。

      已有人將BVDV1細(xì)分為17個基因亞型(1a~1q),BVDV2則分為2a、2b、2e和2d等4個亞型。不同國家和地區(qū)可能有一定的型及亞型優(yōu)勢[7]。但現(xiàn)在的分類方法還有不盡人意之處。Nagai等根據(jù)多基因區(qū)域的差異,對BVDV分離株做進(jìn)化分析[8],發(fā)現(xiàn)一毒株據(jù)5'NCR、N(pro)和E2序列被劃為1e型,而據(jù)NS5B-3'NCR則屬1a型。Gen-Bank中據(jù)5'NCR、N(pro)、E2和NS5B-3'NCR劃歸為1b的2個美國毒株,如按NS3區(qū)分則屬1a。提示對多個編碼區(qū)進(jìn)行進(jìn)化分析更有利于認(rèn)識BVDV野毒分離株。另外,根據(jù)宿主來分類瘟病毒的方法是有缺陷的。對歐洲和新西蘭綿羊瘟病毒的5'NCR片段、P20(Npro)和C編碼區(qū)的片段分析發(fā)現(xiàn),羊不僅可自然感染博爾納病病毒(Borna disease virus,BDV),也能感染BVDV1和2[9]。

      2 BVDV生物型

      根據(jù)BVDV在體外對培養(yǎng)細(xì)胞的致病變性,一般把它分為2種生物型,即致細(xì)胞病變型(cytopathic biotype,CP)和非致細(xì)胞病變型(noncytopathic biotype,NCP),2種生物型屬同一血清型。生物型與急性感染時表現(xiàn)的致病性并不一致,嚴(yán)重急性感染時分離的病毒都屬于NCP型。由于高致病性BVDV急性感染引起去淋巴效應(yīng),Ridpath等根據(jù)BVDV對上皮細(xì)胞和淋巴樣細(xì)胞的反應(yīng)性,提議把BVDV分為3個生物型[10],即非細(xì)胞病變型(對培養(yǎng)上皮細(xì)胞或淋巴樣細(xì)胞的活性無明顯影響)、致細(xì)胞病變型(在感染48 h內(nèi)導(dǎo)致培養(yǎng)上皮細(xì)胞和淋巴樣細(xì)胞發(fā)生病變和死亡)和致淋巴細(xì)胞病變型(對培養(yǎng)上皮細(xì)胞的活性無影響,但在感染5 d內(nèi)使淋巴樣細(xì)胞死亡)。致淋巴細(xì)胞病變型與對動物的高致病性比較一致。

      2.1 生物分型的生物學(xué)意義

      不同生物型在感染細(xì)胞內(nèi)的載量不同,對細(xì)胞功能的影響也明顯不同。不論在傳代細(xì)胞MDBK還是原代PBMC中,CP型的病毒載量明顯高于NCP型[11]。Burr等發(fā)現(xiàn),暴露CP型BVDV后,單核巨噬細(xì)胞數(shù)種關(guān)鍵趨化因子的表達(dá)上調(diào),而與未感染細(xì)胞相比,暴露NCP型BVDV后一些趨化因子下調(diào)[12]。Ammari等報道[13],NCP和CP型病毒感染牛單核細(xì)胞分別引起137和228種蛋白表達(dá)變化。感染CP型BVDV的細(xì)胞中免疫調(diào)節(jié)、凋亡、漿膜信號蛋白及未知功能蛋白相關(guān)的14個基因出現(xiàn)異常。這些基因在NCP型BVDV感染細(xì)胞中的表達(dá)譜與CP型BVDV感染細(xì)胞明顯不同[14]。

      一般認(rèn)為,CP型BVDV可誘導(dǎo)細(xì)胞凋亡,而NCP型BVDV則具有抑制干擾素的能力,從而建立細(xì)胞內(nèi)的持續(xù)感染。Grummer等發(fā)現(xiàn)[15],CP型BVDV誘導(dǎo)培養(yǎng)牛細(xì)胞過表達(dá)凋亡蛋白酶-活化因子1,caspase-9活性明顯增強,提示形成凋亡體,即細(xì)胞感染CP型BVDV導(dǎo)致固有凋亡通路活化。由于CP型BVDV產(chǎn)生的dsRNA量明顯超過NCP型BVDV,完全單獨抑制其他任何一種凋亡相關(guān)細(xì)胞mRNA都能使凋亡減緩,同時沉默2種因子幾乎完全抑制了凋亡而不影響病毒滴度[16],所以形成dsRNA蓄積可能是CP型BVDV感染細(xì)胞凋亡的主要激發(fā)因素。

      Schweizer等報道[17],CP型BVDV誘導(dǎo)牛巨噬細(xì)胞產(chǎn)生IFN-α/β,而NCP型BVDV抑制誘導(dǎo)凋亡及poly(IC)誘導(dǎo)的IFN-α/β表達(dá)。這種活性在病毒蛋白表達(dá)后才展現(xiàn)出來,因而是病毒直接作用的結(jié)果。雖然NCP型BVDV抑制細(xì)胞凋亡及雙鏈RNA誘導(dǎo)的IFN-α/β生成,但2種生物型病毒均不阻斷IFN活性。一旦建立感染,BVDV會對IFN-α/β活性產(chǎn)生抵抗,但不干擾通過IFN-α/β對其他病毒的抵抗機(jī)制[18]。Baigent等也發(fā)現(xiàn)[19],NCP型BVDV感染細(xì)胞不能對dsRNA或感染異種病毒應(yīng)答而產(chǎn)生IFN-α/β或MxA,也不能阻斷CP型BVDV誘導(dǎo)的凋亡。NCP型BVDV感染未調(diào)控細(xì)胞誘導(dǎo)IFN-β轉(zhuǎn)錄因子NF-κB、應(yīng)激激素(JNK1和JNK2)活化或轉(zhuǎn)錄因子ATF-2和c-Jun的磷酸化,但不阻斷SFV或TNFα的相應(yīng)活性。其作用靶分子之一是干擾素調(diào)節(jié)因子3(IRF-3)。Charleston等報道[20],CP型BVDV在體外可誘導(dǎo)Ⅰ型IFN,而NCP型BVDV不能誘導(dǎo)IFN。給胎兒攻擊CP型BVDV能引起IFN產(chǎn)生,而NCP型BVDV則不能。提示,NCP型BVDV抑制誘導(dǎo)Ⅰ型IFN的能力與其在胚胎早期建立持續(xù)感染有關(guān)。

      2.2 生物型的臨床意義

      通過NCP型BVDV建立持續(xù)感染(persistently infected,PI)是維系BVDV在牛群存在的關(guān)鍵。發(fā)生黏膜病的持續(xù)感染??赏瑫r檢測到NCP和CP型BVDV。在PI牛,NCP型BVDV偶而在其NS2突變,形成CP型BVDV變異株,最終引起致死性疾病。Vassilev等發(fā)現(xiàn)[21],黏膜病牛體內(nèi)CP型BVDV和無NS2區(qū)插入序列的配對NCP型BVDV在感染細(xì)胞的病毒蛋白合成水平、生長動態(tài)及病毒產(chǎn)量上并無明顯差異;相反,RNA在CP型病毒感染細(xì)胞內(nèi)的聚積量是NCP型BVDV感染細(xì)胞的25倍以上。CP型病毒是引起宿主病理變化的主要因素。Hewicker-Trautwein等發(fā)現(xiàn)[22],特定CP型BVDV株對胎腦中分化和未分化細(xì)胞均有明顯的嗜向性,所造成的腦病變明顯是細(xì)胞裂解的直接結(jié)果。Gruber等給妊娠65~68 d母羊靜脈接種NCP和CP型BVDV,在胎盤感染的胎兒腦部出現(xiàn)炎性病變及畸形,在感染后14 d內(nèi),只從3只胎羊體內(nèi)檢測到CP型BVDV的RNA。提示CP型BVDV經(jīng)胎盤感染胎羊腦而引起畸形[23]。在暴露PI牛后流產(chǎn)的妊娠母牛,其血液白細(xì)胞層或組織均可檢測到NCP型BVDV,盡管在其血清中出現(xiàn)中和抗體[24]。提示,NCP型BVDV單獨感染也可導(dǎo)致疾病。

      另外,自然或?qū)嶒灨腥綜P型或NCP型BVDV后所產(chǎn)生IgG的特異性基本相似。少數(shù)動物能產(chǎn)生NS3特異的抗體[25]。PI牛暴露抗原異質(zhì)的CP型BVDV后也能發(fā)生牛黏膜病[26]。

      2.3 生物型的遺傳基礎(chǔ)

      一般認(rèn)為,NCP型BVDV缺少一個相對分子質(zhì)量為80×103的多肽,它來源于相對分子質(zhì)量為120×103的多肽,后者在2種生物型中都存在。許多研究證實,CP型病毒是由NCP型病毒基因組通過細(xì)胞基因插入、重復(fù)或重排后形成的。CP型BVDV株經(jīng)過數(shù)次細(xì)胞傳播后,通過相同重復(fù)病毒序列同源重組快速出現(xiàn)NCP型BVDV[27]。多種分子變異與病毒生物型有關(guān),其中影響比較大的是游離NS3的表達(dá)。一般CP型BVDV都表達(dá)獨立的 NS3,而 NCP型 BVDV僅表達(dá) NS2-3。Kümmerer等指出[28],BVDV的致細(xì)胞病變性與NS3的表達(dá)有關(guān)。CP型BVDV Oregon株NS2-3加工是由NS2內(nèi)一組點突變引起的,給野毒基因引入該NS2基因足夠引起NS2-3加工及表現(xiàn)CP型表型。第1555位絲氨酸對NS2-3裂解效率有重要影響。多個CP型株有一個完整泛素基因或細(xì)胞源mRNA序列插入及病毒重復(fù)序列,而相應(yīng)的NCP型基因組中無細(xì)胞插入及重復(fù)[29-39]。有的插入片段可誘導(dǎo)NS2-3裂解[37,40-41],有的不僅調(diào)節(jié)NS3生產(chǎn)還上調(diào)RNA復(fù)制[36],但也有的插入不影響病毒的復(fù)制及NS2-3加工[35]。產(chǎn)生NS3均是病毒致細(xì)胞病變性的起因。Kameyama等報道[42],CP型BVDV感染后,其NS2-3在感染細(xì)胞內(nèi)被切割,而NCP型BVDV感染時不能切割。在NCP型BVDV感染的PI胎牛肌細(xì)胞中可檢測到NS2-3蛋白。另一方面,在這些PI牛的白細(xì)胞中可見NS2-3的裂解產(chǎn)物,在PI牛淋巴、腦、甲狀腺、肺和腎中都可檢測到NS3,提示一些NCP型BVDV的NS2-3蛋白可在體內(nèi)切割。

      Becher等發(fā)現(xiàn)一個編碼NS3、NS4A和NS4B序列的重復(fù)甚至影響到病毒對溫度的敏感性[43]。Tautz等發(fā)現(xiàn),數(shù)株CP型BVDV的基因組含泛素編碼序列(ucs),而NCP型BVDV無此插入[44]。ucs插入和致死性疾病的發(fā)生存在直接關(guān)系。Greiser-Wilke等篩查16株CP型BVDV的p125基因區(qū)RNA插入和/或p80基因重復(fù),發(fā)現(xiàn)有3株含插入,另有3株帶基因重復(fù),1株既有插入也有重復(fù),而10株NCP型BVDV未檢測到插入或重復(fù)序列[45]。表明RNA插入和基因重復(fù)并不是體外致細(xì)胞病變性的惟一機(jī)制。Ridpath等的研究也得到相似結(jié)論[46]。

      綜上所述可以看出,BVDV的生物型與其致病性有密切關(guān)系,而表型的形成是由病毒的基因變異引起的。基因變異還能改變病毒的其他生物特性,如溫度敏感性。高致病毒株的出現(xiàn)將對該病的防控帶來新問題,但目前對這方面的遺傳學(xué)規(guī)律還了解較少,因而深入研究BVDV的分子流行病學(xué)是非常必要的。

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      Genetic Basis of the Biotype of Bovine Viral Diarrhea Virus

      MENG Qing-Sen1,LIU Fang-Fang1,MENG Xiang-Qiu2, SHI Xin-Chuan1,ZHAO Jian-Zeng1,2*

      1.Sinovet(Jiangsu)Biopharmaceuticals Co.,Ltd,Taizhou 225300;
      2.Sinovet(Beijing)Biotechnology Co.,Ltd,Beijing 100085;China

      *Corresponding author,E-mail:zhaojianzeng@sinovetah.com

      Bovine viral diarrhea virus(BVDV),a member ofPestivirusof very important veterinary significance, is now becoming a major pathogen and causes substantial economic losses every year to global cattle industry.Infections with BVDV usually cause diarrhea and reproductive disorders and other health problems resulting from immunosuppression.Biologically,BVDV could be divided into two biotypes according to its pathogenicity to the cellsin vitro.Complex genetics variations and post-translation processing of the viral proteins constitute the mechanisms of biotype development.And the knowledge in this field will help us to predicate the evolution of the pathogenicity of the virus and to make comparable strategy to control the disease.In this paper we reviewed the advances in research figuring out the relationship of biotype,pathogenicity and gene variation of BVDV.

      bovine viral diarrhea virus;biotype;gene variation

      S852.65

      A

      1009-0002(2017)03-0382-06

      10.3969/j.issn.1009-0002.2017.03.028

      2016-11-21

      孟慶森(1985-),男,碩士研究生,(E-mail)mengqingsen@sinovetah.com

      趙建增,(E-mail)zhaojianzeng@sinovetah.com

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