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Infection and immune response

Infection and immune response. Bing Sun, MD, Ph.D Lab of Molecular Virology, Institute of Pasteur of Shanghai, Chinese Academy of Science. Tel:63851927. Fax:bsun@sibs.ac.cn. H13. H3 H4. H1 H1´ H3. H3 H7. H1 H2 H3 B ?. H5 H6 H7 H9. Interspecies transmission of influenza viruses.

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Infection and immune response

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  1. Infection and immune response Bing Sun, MD, Ph.D Lab of Molecular Virology, Institute of Pasteur of Shanghai, Chinese Academy of Science. Tel:63851927. Fax:bsun@sibs.ac.cn

  2. H13 H3 H4 H1 H1´ H3 H3 H7 H1 H2 H3 B ? H5 H6 H7 H9 Interspecies transmission of influenza viruses - Occasional transmissions with outbreaks of various severity - On rare occasions, adaptation to new species and establishing of stable virus lineages - Transmission to humans of antigenically new virus can initiate pandemic H5, H7 or H9??

  3. U.S. Life Expectancy By age 70 60 50 40 30 1900 ‘50 ‘70 ‘90 ‘30 The Impact of the Spanish Influenza 1918 pandemic strian (H1N1) 20-40 million deaths worldwide Nature. Oct. 6, 2005 confirm its strong pathogenesis

  4. From 1997, sporadic human infection with avian influenza viruses has raised concern that reassortment between human and avian subtypes could generate viruses of pandemic potential.

  5. PB1 PB2 PA HA NP NA M1 M2 NS1 NS2 高致病禽流感病毒蛋白特性分析 Negative strand RNA virus RNA多聚酶 病毒进入细胞 RNA多聚酶 病毒释放 病毒RNA包装 离子通道，进入细胞 抑制宿主免疫反应 了解病毒蛋白与宿主细胞的相互作用，探讨可能的分子 机制，对发现新药有重要的指导意义。

  6. I. Research on pathogenesis of avian influenza host-pathogen interactions • NS1 is known to suppress IFN-a/b production in host in order to facility virus replication

  7. Mechanism • glutamic acid at position 92 of the NS1 molecule is essential Seo, S.H., Hoffmann, E. & Webster, R.G. Nature Med. 2002

  8. TLR signaling pathway LPS/PTX， TCS（allergens） New family genes

  9. Mechanism Xiuyan Wang , J Virol. , 2000 December

  10. Scientific Question • Whether NS1 gene contribute to the pathogenesis • Whether NS1 gene function is different between H5N1(high pathogenic) and H9N2(low pathogenic) • Is glutamic acid at position 92 is essential for this phenomena • What is the molecular mechanism that NS1 can suppress IFN production

  11. Strategy to address the question • check out pseudovirus infection under NS1 gene existing • Yeast two hybridize to check out what host’s gene can interact with NS1 • comparison antagonize ability between NS1 from H5 and H9 subtypes • 92 position mutation to see whether this is essential

  12. Strategy 1:check out pseudovirus infection activity Propose: 1. HIV basedpseudovirus can be used as a dsRNA stimulation that can evoke type I IFN production from target cells and virus infection activity can be evaluated by luciferase value . 2. When target cells can express NS1 , it can suppress IFN production and then facility virus infection. generation of pseudovirus with vsv-G CNE1 cells temporarily expressing NS1 gene infect NS1 vector normal

  13. NS1 gene can increase virus infection Virus infection activity in CNE1 cells express or not NS1 gene from H5N1

  14. Summary • 1. NS1 play an important role in controlling pseudovirus replication. • 2.There is no significantly difference between NS1 from H5N1 and H9N2 to induce NF-kB and ISRE activation. • 3. We still try to find other host factors that modulated NS1 function and control IFN-a production .

  15. Th1/Th2 cells 对诱导免疫应答和疾病的发生有重要的作用 Th1/Th2理论的发展 经历了三个阶段： 1、验证Th1/Th2细胞 克隆的存在。 2、验证Th1/Th2细胞 与疾病的关系。 3、 Th1/Th2细胞转录 因子和新分子的 研究。 这些对Th1/Th2细胞 分化机制研究有重要 的科学意义。 器官特异性自身免疫病, 器官排斥反应，抗感染 和一些抗肿瘤免疫反应 系统性自身免疫病, 过敏性疾病，哮喘

  16. 二、科学问题的提出 Th1- cell 病原体或抗原 Naïve T-cell 未成熟DC 成熟DC ????? Th2- cell 1、DC如何调节T细胞的分化机制是不清楚的。 2、Naïve T细胞分化为Th1/Th2细胞机制和其效应的新分 子需要不断充实完善。(复杂、精细性) IFN-g TNF-a T-bet, STAT4, Hlx ????? 新的转录因子 效应分子????? 1 2 GATA3, STAT6,c-maf IL-4,IL-5 IL-13

  17. DCs are only cells to activate naive T cells and provide the necessary signals to stimulated T cells. Costimulatory molecules B7-1,B7-2 CD28,CTLA-4 (Signal two) Naive T cell (Signal one) TCR MHC class I & II Cytokines/chemokines (IL-12) and Membrane molecules (receptors) Epitopes of Ag DNA microarray and proteomics are used to analyzed PTX-DC和TCS-DC gene profiles and identify novel genes regulating DC maturation and T cell activation.

  18. Potential genes for NF-kB activation

  19. Potential genes related with IFN

  20. Trim30a expression was inhibited by NF-kB inhibitors • BM-DC • J774

  21. Mol Cell. 2004 Aug 27;15(4):535-48. Conclusion of Part I • Trim30a is induced by TLR agonists and its expression depends on NF-kB activity. • Trim30a is [directly] interacted with tak1 and results in the instability of tab2. • This modulates the TLR signaling.

  22. Retrovirus system

  23. MSCV-Trim30a inhibits virus infection

  24. Transient express trim30a • NIH3T3

  25. Summary • Trim 30a is new functional protein and negatively regulate NF-kB signal and may have function to anti-virus.

  26. Thanks! Thanks!

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