1、Alphaherpesviruses Infection and its Evasion of Host Innate Immunity,http:/ Chunfu Zheng, Ph. D.,Scientific interests,HSV-1逃逸宿主天然免疫/获得性免疫的分子机制；HSV-1与宿主相互作用的分子机制；,Herpes Simplex viruses type I I型单纯疱疹病毒,自我介绍,1991年中国农大本科，2001年重庆医大博士，2001-2007, 博士后（加拿大）2007-2012, 中科院武汉病毒研究所,百人计划2013-至今，苏州大学，特聘教授Journal
2、of Virology 编委（2015-17）（截至2014，没有一位编委来自中国大陆的科学家/病毒学家）作为唯一一位中国科学家/病毒学家连续3届担任国际疱疹病毒研讨会科学顾问委员会委员（2012-4）在Journal of Virology发表10余篇高质量的论文，揭示了HSV-1逃逸宿主天然免疫的多种新机制。,Virology,Section I,Human Herpes Viruses (HHV),Nat. Rev. Immunol.2011,11:143,Animal Herpes Viruses (AHV),Pseudorabies Virus (PRV) Bovine Herpes
3、 Virus (BHV) Mareks 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 available Painful failure of promising genital herpes vaccine. Science.2010 Phase III trial failure. N Engl J Med. 20
4、12 HSV-1 infection: 100% serum positive latency Pathogenesis: Cold sore, zosteriform 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 changes Stress,
5、 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/HHV3),Pathogenesis Chickenpox Herpes zoster (shingles) Vaccination Oka strain: 1974; 1995 Zostavax: 2005 (50%),Core
6、viral DNACapsid 162 capsomers VP5, VP26, VP23, VP19C,Virion Structure,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: Internal repeatsa: Sequences required for packagi
7、ng,Immediate early, IE, regulation of gene transcriptionEarly, E, transcription factors enzymesLate, L, structural proteins,13,The expression of HSV-1 gene,Essential and Accessory Genes,Accessory, Non-essential Essential,14,Viral entry,1. Attachment or Viral Adsorption2. Membrane Fusion or Hemifusio
8、n State3. Entry Pore formation4. Viral Penetration,gB, gC, 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 period Stage 3: Recurrence
9、,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 stress and anxiety,19,Host Immunity and Viral Immune Evasion,Section II,病毒与宿主的博弈,PRRs and HSV-1/VZV,Nat. Rev. Immuno
10、l. 2011,11:143,cGAS: Genomic DNA,Toll-like Receptor Signaling,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,HSVs interfere with
11、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,结构和非结构蛋白作为靶分子 囊膜蛋白：gB、gC、gD、gE、gH 衣壳和皮层蛋白：VP11/12、VP13/14、VP16、VP22、VP5 非结构蛋白：dUTPase和ICP8,CD4+T细胞,CTL IFN- Granzyme B
12、CD8+T细胞：潜伏感染的维持 三叉神经节周围大量存在，监视 潜伏状态病毒使其不被激活,CD8+T细胞,由膜蛋白(糖蛋白)诱导产生 中和抗体：鉴别HSV-1/HSV-2 中和抗体：原发感染、再感染 中和抗体：对病毒的免疫逃逸起促进作用,特异性抗体反应,I 型干扰素 （IFN-/） 自然杀伤细胞 （NK） 巨噬细胞 （M） 树突状细胞 （DC） 中性粒细胞等,天然免疫反应,I 型干扰素,感染后数小时内即可产生（TLR、RLR） 由病毒蛋白及核酸诱导产生 dsDNA以及DNA复制的中间产物，如dsRNA 显著抑制HSV-1的复制和感染 （ISG） 诱导和上调获得性免疫，尤其是特异性细胞免疫,自然杀
13、伤细胞(NK),抗HSV感染的重要效应细胞(CTL) 快速分泌IFN-及其它细胞因子,调节免疫应答 IFN-: 增强NK细胞的杀伤作用,直接吞噬入侵的病毒 通过其表面Fc受体吞噬各种病毒复合物 分泌精氨酸酶抑制病毒复制 降解邻近感染细胞中病毒复制必需的精氨酸,巨噬细胞（M）,Plasmacytoid dendritic cells, pDCs,产生I 型干扰素 组成型表达IRF-7 HSV-1可诱导pDCs产生大量IFN-,利用宿主的免疫豁免组织 诱导免疫抑制 干扰宿主细胞的抗原递呈 干扰淋巴因子网络 干扰补体系统,HSV-1 is a “smart” virus,利用宿主的免疫豁免组织,神经
14、元：建立潜伏感染 神经元：逃避宿主免疫监控 潜伏感染：不产生可检测抗原,诱导免疫抑制,激活p38和JNK/MAPK,上调IL-10 抑制TCR下游Stat3通路的激活,ICP47 干扰TAP复合体 阻断MHC-I类分子在ER及其它细胞器之间的转运和成熟, 从而抑制MHC-I类分子功能 VHS（virus-host-shutoff）蛋白-UL41,干扰 MHC I类分子,HSV感染下调感染细胞表面MHC-II分子 半衰期明显缩短 VHS和ICP34.5与此有关 VHS直接影响细胞蛋白合成，阻断MHC-II类分子递呈 gB：干扰Ag肽段向MHC-II类分子复合物的装载,干扰 MHC-II类分子,g
15、C能够以受体形式结合补体级联激活途径的 C3b，从而阻断C3b所引发的级联酶促反应 gE-gI能够形成二聚体影响Fc受体介导的 补体病毒中和作用,干扰补体系统,NKT细胞可被感染细胞表面递呈的CD1d分子 激活，杀伤靶细胞 HSV感染影响CD1d在细胞内的转运、回收再利用 感染细胞的抗原递呈效率明显下降,干扰NKT细胞,Section ,Studies in our lab,IFN- signalling pathway,Annu. Rev. Immunol. 2014. 32:51345,US11,US3 ORF61,ICP0, UL42 US3,UL41,UL36USP,JVI, 2011
16、; 2012; 2013 a, b, c, d; 2014 a, b,CBP/P300,CBP/P300,VP16,Summary,Acknowledgements,Funds: NSFC；973 program,Evasion of IFN- 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
17、 recruitment of TBK1,Wang 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 nuclear translocation and dimerization of IRF-3,Xing JJ et al. JVI.
18、 2013,VP16 blocks IRF-3CBPDNA complex formation,VP16 inhibits the interaction between endogenous IRF-3 and CBP in the context of HSV-1 infection.,Xing JJ et al. JVI. 2013,5. HSV-1 ICP0 inhibits TNF- mediated NF-B 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 interested?,Join us ! 为人类的健康做出微薄贡献！ 就业前景： 出国博士后； 高校教师； 研究所； 生物制药相关的企业； ,
