皰疹病毒感染與免疫逃逸研究生

1、Alphaherpesviruses Infection and its Evasion of Host Innate Immunity,http://ibms.suda.edu.cn/html/ChunFuZhengLab/Chunfu.zheng@suda.edu.cn,Dr. Chunfu Zheng, Ph. D.,Scientific interests,HSV-1逃逸宿主天然免疫/獲得性免疫的分子機(jī)制；HSV-1與宿

2、主相互作用的分子機(jī)制；,Herpes Simplex viruses type I I型單純皰疹病毒,自我介紹,1991年中國(guó)農(nóng)大本科，2001年重慶醫(yī)大博士，2001-2007, 博士后（加拿大）2007-2012, 中科院武漢病毒研究所,百人計(jì)劃2013-至今，蘇州大學(xué)，特聘教授Journal of Virology 編委（2015-17）（截至2014，沒有一位編委來自中國(guó)大陸的科學(xué)家/病毒學(xué)家）作為唯一一位中國(guó)科

3、學(xué)家/病毒學(xué)家連續(xù)3屆擔(dān)任國(guó)際皰疹病毒研討會(huì)科學(xué)顧問委員會(huì)委員（2012-4）在Journal of Virology發(fā)表10余篇高質(zhì)量的論文，揭示了HSV-1逃逸宿主天然免疫的多種新機(jī)制。,Virology,Section I,Human Herpes Viruses (HHV),Nat. Rev. Immunol.2011,11:143,Animal Herpes Viruses (AHV),Pseudorabies Virus

4、(PRV) Bovine Herpes Virus (BHV) Marek’s Disease Virus (MDV) Monkey, fish, ….,HSV-1,First identified herpesvirus Institutes：4199 ? 100 papers: 88 ? 16 papers: 500 ? 50 papers：38 ? 6 papers：500,HSV-1/2: no vaccine

5、 available Painful failure of promising genital herpes vaccine. Science. 2010  Phase III trial failure. N Engl J Med. 2012 HSV-1 infection: 100% serum positive latency Pathogenesis: Cold sore, zoster

6、iform skin lesions, pneumonia, systemic infections HSV-1 keratitis (HSK); Blindness Encephalitis/AD: TLR3/UNC93B1/TRAF3/TRIF Stressor: Viral infection (other viruses) Nerve trauma, Physiologic and physical

7、changes Stress, fever, menstruation, and UV light HSV-1 genital infection 60% Gene therapy vector: tumor, neural system diseases, pain,Herpes Simplex Virus type 1 (HSV-1),Varicella Zoster Virus (VZV/HH

8、V3),Pathogenesis Chickenpox Herpes zoster (shingles) Vaccination Oka strain: 1974; 1995 Zostavax: 2005 (50%),Core viral DNACapsid 162 capsomers VP5, VP26, VP23, VP19C,Virion Structure,

9、Tegument ? 20 proteins;Envelope A lipid bilayer ? 11 glycoproteins,The organization of the HSV-1 genome (152 kb),UL: Unique long regions US: Unique short regionsTR: Terminal repeatsIR: Interna

10、l repeats‘a(chǎn)’: Sequences required for packaging,Immediate early, IE, α regulation of gene transcriptionEarly, E, β transcription factors enzymesLate, L, γ structural proteins,13,The expression of HSV-1

11、gene,Essential and Accessory Genes,Accessory, Non-essential Essential,14,Viral entry,1. Attachment or Viral Adsorption2. Membrane Fusion or Hemifusion State3. Entry Pore formation4. Viral Penetration,gB, gC,

12、 gD, gH, gL,The lytic replication cycle,Nat. Rev. Immunol.2011,11:143,Adsorption and penetration Uncoating Biosynthesis Assembly and release,Three stages of HSV-1 infection,Stage 1: Primary infectionStage 2: Latency

13、 period Stage 3: Recurrence,17,Treatment of HSV-1,Antiviral medicationsPain relief medications Topic antibiotics,18,Prevention of HSV-1,Personal hygieneAvoid drinking alcohol, smoking and eating spicy foodAvoid st

14、ress and anxiety,19,Host Immunity and Viral Immune Evasion,Section II,病毒與宿主的博弈,PRRs and HSV-1/VZV,Nat. Rev. Immunol. 2011,11:143,cGAS: Genomic DNA,Toll-like Receptor Signalin

15、g,HSV infection and TLR,Herpes. 2006; 13(2):37-41,HSVs interfere with host detection of viral determinants,Mediators Inflammation. 2015:593757,gB,gB,HSVs interfere with cell viability,Mediators Inflammation. 2015:593757

16、,HSVs interfere with the induction of type-I interferons and interferon signaling,Mediators Inflammation. 2015:593757,Adaptive immunity response after HSV-1 infection,CD4+T cells CD8+T cells Antibodies,結(jié)構(gòu)和非結(jié)構(gòu)蛋白作為靶分子

17、 囊膜蛋白：gB、gC、gD、gE、gH 衣殼和皮層蛋白：VP11/12、VP13/14、VP16、VP22、VP5 非結(jié)構(gòu)蛋白：dUTPase和ICP8,CD4+T細(xì)胞,CTL IFN-γ Granzyme B CD8+T細(xì)胞：潛伏感染的維持 三叉神經(jīng)節(jié)周圍大量存在，監(jiān)視 潛伏狀態(tài)病毒使其不被激活,CD8+T細(xì)胞,由膜蛋白(糖蛋白)誘導(dǎo)產(chǎn)生 中和抗體：鑒別HSV-1/HSV-2 中和抗體：原發(fā)感染、再感染 中

18、和抗體：對(duì)病毒的免疫逃逸起促進(jìn)作用,特異性抗體反應(yīng),I 型干擾素 （IFN-α/β） 自然殺傷細(xì)胞 （NK） 巨噬細(xì)胞 （M?） 樹突狀細(xì)胞 （DC） 中性粒細(xì)胞等,天然免疫反應(yīng),I 型干擾素,感染后數(shù)小時(shí)內(nèi)即可產(chǎn)生（TLR、RLR） 由病毒蛋白及核酸誘導(dǎo)產(chǎn)生 dsDNA以及DNA復(fù)制的中間產(chǎn)物，如dsRNA 顯著抑制HSV-1的復(fù)制和感染 （ISG） 誘導(dǎo)和上調(diào)獲得性免疫，尤其是特異性細(xì)胞免疫,自然殺傷細(xì)胞(NK),

19、抗HSV感染的重要效應(yīng)細(xì)胞(CTL) 快速分泌IFN-γ及其它細(xì)胞因子,調(diào)節(jié)免疫應(yīng)答 IFN-γ: 增強(qiáng)NK細(xì)胞的殺傷作用,直接吞噬入侵的病毒 通過其表面Fc受體吞噬各種病毒復(fù)合物 分泌精氨酸酶抑制病毒復(fù)制 降解鄰近感染細(xì)胞中病毒復(fù)制必需的精氨酸,巨噬細(xì)胞（M?）,Plasmacytoid dendritic cells, pDCs,產(chǎn)生I 型干擾素 組成型表達(dá)IRF-7 HSV-1可誘導(dǎo)pDCs產(chǎn)生大量IFN-α,

20、利用宿主的免疫豁免組織 誘導(dǎo)免疫抑制 干擾宿主細(xì)胞的抗原遞呈 干擾淋巴因子網(wǎng)絡(luò) 干擾補(bǔ)體系統(tǒng),HSV-1 is a “smart” virus,利用宿主的免疫豁免組織,神經(jīng)元：建立潛伏感染 神經(jīng)元：逃避宿主免疫監(jiān)控  潛伏感染：不產(chǎn)生可檢測(cè)抗原,誘導(dǎo)免疫抑制,激活p38和JNK/MAPK,上調(diào)IL-10 抑制TCR下游Stat3通路的激活,ICP47 干擾TAP復(fù)合體 阻斷MHC-I類分子在ER及

21、其它細(xì)胞器之間的轉(zhuǎn)運(yùn)和成熟, 從而抑制MHC-I類分子功能 VHS（virus-host-shutoff）蛋白---UL41,干擾 MHC I類分子,HSV感染下調(diào)感染細(xì)胞表面MHC-II分子 半衰期明顯縮短 VHS和ICP34.5與此有關(guān) VHS直接影響細(xì)胞蛋白合成，阻斷MHC-II類分子遞呈 gB：干擾Ag肽段向MHC-II類分子復(fù)合物的裝載,干擾 MHC-II類分子,gC能夠以受體形式結(jié)合補(bǔ)體級(jí)聯(lián)激活途徑的 C3

22、b，從而阻斷C3b所引發(fā)的級(jí)聯(lián)酶促反應(yīng) gE-gI能夠形成二聚體影響Fc受體介導(dǎo)的 補(bǔ)體病毒中和作用,干擾補(bǔ)體系統(tǒng),NKT細(xì)胞可被感染細(xì)胞表面遞呈的CD1d分子 激活，殺傷靶細(xì)胞 HSV感染影響CD1d在細(xì)胞內(nèi)的轉(zhuǎn)運(yùn)、回收再利用 感染細(xì)胞的抗原遞呈效率明顯下降,干擾NKT細(xì)胞,Section Ⅲ,Studies in our lab,IFN-β signalling pathway,Annu. Rev. Immuno

23、l. 2014. 32:513–45,,,US11,US3 ORF61,ICP0, UL42 US3,UL41,,,,,,UL36USP,,,,,JVI, 2011; 2012; 2013 a, b, c, d; 2014 a, b,,CBP/P300,,CBP/P300,,,,VP16,,,,,,,Summary,Acknowledgements,Funds: NSFC；973 program,Evasion of IFN-β

24、 Signaling pathway by HSV-1,US11,,,UL36USP,,,ICP34.5,,,ICP0, US3 VZV ORF61,,,VP16,,,ICP0,,,,,,,1. US11 impedes IRF3 activation,Xing, et al. JVI 2012,2. UL36USP deubiquitinates TRAF3 and inhibits recruitment of TBK1,,W

25、ang S et al. JVI. 2013 a,3. US3 inhibits the dimerization and nuclear translocation of IRF3,K220: ATP bindingD305: catalytic activity,,Wang S et al. JVI. 2013 b,4. VP16 interacts with IRF3 but does not block the nu

26、clear translocation and dimerization of IRF-3,,,Xing JJ et al. JVI. 2013,VP16 blocks IRF-3–CBP–DNA complex formation,VP16 inhibits the interaction between endogenous IRF-3 and CBP in the context of HSV-1 infection.,Xing

27、 JJ et al. JVI. 2013,5. HSV-1 ICP0 inhibits TNF-α mediated NF-κB activation,,Zhang J et al. JVI. 2013,6. ICP0 interacts with and degrades p50 through the ubiquitin-proteasome pathway,Zhang J et al. JVI. 2013,Are you i