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创新研究群体项目获得者

张立国博士研究员博士生导师

中科院生物物理所，中科院感染与免疫重点实验室，研究组长

研究方向：艾滋病及慢性病毒性肝炎的人源化小鼠模型；浆样树突状细胞及其在病毒感染中的作用。

电子邮件：liguozhang@ibp.ac.cn

电话：010-64862568

通讯地址：北京市朝阳区大屯路15号（100101）

英文版个人网页：http://english.ibp.cas.cn/sourcedb/rck/EN_xsszmZ/202005/t20200519_341362.html

简历：

　　1990.09 - 1994.06 河北农业大学，兽医学，学士

　　1994.09 - 1997.06 南京农业大学，兽医微生物及免疫学，硕士

　　1997.09 - 2000.06 中国预防医学科学院病毒学研究所，病原生物学，博士

　　2000.09 - 2002.04 中国预防医学科学院病毒学研究所，助理研究员，主要从事流感病毒疫苗研究工作

　　2002.05 - 2005.10 美国耶鲁大学医学院，博士后，研究鼠细小病毒(Minute Virus of mice)基因组复制机理和病毒载体

　　2005.11 - 2008.06 美国北卡大学教堂山分校，博士后，人免疫缺陷病毒（HIV）致病机理，构建HIV感染的人源化小鼠模型

　　2008.07 - 至今中国科学院生物物理研究所，研究员

获奖及荣誉：

社会任职：

研究方向：

　　艾滋病的人源化小鼠模型：艾滋病是由人免疫缺陷病毒（HIV）感染所引起的以CD4辅助性T细胞减少为特征的传染病。没有合适的动物模型是制约艾滋病研究的重要因素之一。我们利用严重免疫缺陷的小鼠（Rag2-/-gammaC-/-），通过移植人的造血干细胞，构建了免疫系统人源化的小鼠模型。移植细胞在小鼠体内发育成为人的各种免疫细胞，并能够在抗原的刺激下产生功能性的免疫应答。HIV能够感染人源化的小鼠并杀伤CD4＋ T 淋巴细胞。利用这一模型，我们初步开展了HIV致病机理、变异规律以及抗病毒药物的研究。在此基础之上，我们将进一步研究HIV感染的致病机理，主要是浆样树突状细胞（pDC）在HIV感染中的作用（见下面pDC的相关介绍）。

　　浆样树突状细胞及其在病毒感染中的作用：浆样树突状细胞（pDC）高表达Toll样受体7（TLR7）和TLR9，在病毒或其他刺激下能够产生大量Ⅰ型干扰素，并成熟为抗原提成细胞（APC）。它产生Ⅰ型干扰素的能力是其它细胞的100-1000倍，因此又被称为干扰素产生细胞。近年来的研究表明，虽然pDC在人的外周血中的比例仅为0.2-0.5%，但它在抗感染免疫，自身免疫病和肿瘤免疫中都起着非常重要的作用。在病毒感染中，它通过TLR7和TLR9分别识别病毒的RNA和DNA，释放大量干扰素和炎性因子，激活NK细胞和髓样树突状细胞（mDC）等其他天然免疫细胞；成熟为APC之后又能活化T细胞，启动适应性免疫。关于pDC，我们对以下两方面感兴趣：1. pDC产生干扰素和炎性因子的分子机制；2. 在HIV、HBV等病毒感染中，pDC在免疫逃逸和免疫病理中的作用。

承担项目情况：

代表论著：

Research papers

1. Cheng L, Ma J, Li J, Li D, Li G, Li F, Zhang Q, Yu H, Yasui F, Ye C, Tsao LC, Hu Z, Su L, Zhang L (2017) Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs. J Clin Invest 127(1):269-279.

2. Zhang X, Yang P, Wang N, Zhang J, Li J, Guo H, Yin X, Rao Z, Wang X, Zhang L (2017) The binding of a monoclonal antibody to the apical region of SCARB2 blocks EV71 infection. Protein Cell 8(8):590-600.

3. Yin X, Yu H, Jin X, Li J, Guo H, Shi Q, Yin Z, Xu Y, Wang X, Liu R, Wang S, Zhang L (2017) Human Blood CD1c+ Dendritic Cells Encompass CD5high and CD5low Subsets That Differ Significantly in Phenotype, Gene Expression, and Functions. J Immunol 198(4):1553-1564.

4. Li J1, Du Q, Hu R, Wang Y, Yin X, Yu H, Du P, Plumas J, Chaperot L, Liu YJ, Zhang L (2016) Death receptor 6 is a novel plasmacytoid dendritic cell-specific receptor and modulates type I interferon production. Protein Cell 7(4):291-4. doi: 10.1007/s13238-015-0239-0.

5. Ma J, Yu H, Yin X, Cheng M, Shi Q, Yin Z, Nie X, Shouli W, Zhang L (2015) E2-2, a novel immunohistochemical marker for both human and monkey plasmacytoid dendritic cells. Biophys Rep 1:139-147. doi: 10.1007/s41048-016-0023-6. Epub 2016 Apr 11

6. Guo H, Zhang J,Zhang X, and Zhang L (2015) SCARB2/LIMP-2 Regulates IFN Production of Plasmacytoid Dendritic Cells by Mediating Endosomal Translocation of TLR9 and Nuclear Translocation of IRF7. J Immunol 194(10): 4737–4749.

7. Cheng M, Zhang X, Yu H, Du P, Plumas J, Chaperot L, Su L, Zhang L (2015) Characterization of species-specific genes regulated by E2-2 in human plasmacytoid dendritic cells. Sci Rep 17;5:10752. doi: 10.1038/srep10752.

8. Li G, Cheng M, Nunoya J, Cheng L, Guo H, Yu H, Liu YJ, Su L & Zhang L (2014) Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice. PLoS Pathog 10, e1004291.

9. Hu R, Du Q, Yin X, Li J, Wang T & Zhang L (2014) Agonist antibody activates death receptor 6 downstream signaling involving TRADD recruitment. FEBS Lett 588, 401-407.

10. Yang D, Liu L, Zhu D, Peng H, Su L, Fu YX & Zhang L (2014) A mouse model for HBV immunotolerance and immunotherapy. Cell Mol Immunol 11, 71-78.

11. Li F, Cowley DO, Banner D, Holle E, Zhang L & Su L (2014) Efficient genetic manipulation of the NOD-Rag1-/-IL2RgammaC-null mouse by combining in vitro fertilization and CRISPR/Cas9 technology. Sci Rep 4, 5290.

12. Dang M, Wang X, Wang Q, Wang Y, Lin J, Sun Y, Li X, Zhang L, Lou Z, Wang J, et al. (2014) Molecular mechanism of SCARB2-mediated attachment and uncoating of EV71. Protein Cell doi: 10.1007/s13238-014-0087-3.

13. Bility MT, Cheng L, Zhang Z, Luan Y, Li F, Chi L, Zhang L, Tu Z, Gao Y, Fu Y, Su L. (2014) Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages. PLoS Pathog 10, e1004032.

14. Ru H, Zhao L, Ding W, Jiao L, Shaw N, Liang W, Zhang L, Hung LW, Matsugaki N, Wakatsuki S, et al. (2012) S-SAD phasing study of death receptor 6 and its solution conformation revealed by SAXS. Acta Crystallogr D Biol Crystallogr 68, 521-530.

15. Ma JP, Xia HJ, Zhang GH, Han JB, Zhang L & Zheng YT (2012) Inhibitory effects of chloroquine on the activation of plasmacytoid dendritic cells in SIVmac239-infected Chinese rhesus macaques. Cell Mol Immunol 9(5):410-6.

16. Bility MT, Zhang L, Washburn ML, Curtis TA, Kovalev GI & Su L (2012) Generation of a humanized mouse model with both human immune system and liver cells to model hepatitis C virus infection and liver immunopathogenesis. Nat Protoc 7, 1608-1617.

17. Du Q, Jiao Y, Hua W, Wang R, Wei F, Ji Y, Du P, Liu YJ, Wu H & Zhang L (2011) Preferential depletion of CD2(low) plasmacytoid dendritic cells in HIV-infected subjects. Cell Mol Immunol 8, 441-444.

18. Zhang L, Jiang Q, Li G, Jeffrey J, Kovalev GI & Su L (2011) Efficient infection, activation, and impairment of pDCs in the BM and peripheral lymphoid organs during early HIV-1 infection in humanized rag2(-)/(-)gamma C(-)/(-) mice in vivo. Blood 117, 6184-6192.

19. Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A, Frelinger JA, Barry W, Ploss A, Rice CM & Su L (2011) A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology 140, 1334-1344.

20. Sivaraman V, Zhang L & Su L (2011) Type I interferon contributes to CD4⁺ T cell depletion induced by infection with HIV-1 in the human thymus. J Virol 85, 9243-9246.

21. Ince WL, Zhang L, Jiang Q, Arrildt K, Su L & Swanstrom R (2010) Evolution of the HIV-1 env gene in the Rag2-/- gammaC-/- humanized mouse model. J Virol 84, 2740-2752.

22. Sivaraman V, Zhang L, Meissner EG, Jeffrey JL & Su L (2009) The heptad repeat 2 domain is a major determinant for enhanced human immunodeficiency virus type 1 (HIV-1) fusion and pathogenicity of a highly pathogenic HIV-1 Env. J Virol 83, 11715-11725.

23. Choudhary SK, Rezk NL, Ince WL, Cheema M, Zhang L, Su L, Swanstrom R, Kashuba AD & Margolis DM (2009) Suppression of human immunodeficiency virus type 1 (HIV-1) viremia with reverse transcriptase and integrase inhibitors, CD4⁺ T-cell recovery, and viral rebound upon interruption of therapy in a new model for HIV treatment in the humanized Rag2-/-{gamma}c-/- mouse. J Virol 83, 8254-8258.

24. Jiang Q, Zhang L, Wang R, Jeffrey J, Washburn ML, Brouwer D, Barbour S, Kovalev GI, Unutmaz D & Su L (2008) FoxP3+CD4+ regulatory T cells play an important role in acute HIV-1 infection in humanized Rag2-/-gammaC-/- mice in vivo. Blood 112, 2858-2868.

25. Holmes D, Jiang Q, Zhang L & Su L (2008) Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis. Immunol Res 41, 248-266.

26. Zhang L, Kovalev GI & Su L (2007) HIV-1 infection and pathogenesis in a novel humanized mouse model. Blood 109, 2978-2981.

27. Meissner EG, Zhang L, Jiang S & Su L (2006) Fusion-induced apoptosis contributes to thymocyte depletion by a pathogenic human immunodeficiency virus type 1 envelope in the human thymus. J Virol 80, 11019-11030.

28. Farr GA, Zhang L & Tattersall P (2005) Parvoviral virions deploy a capsid-tethered lipolytic enzyme to breach the endosomal membrane during cell entry. Proc Natl Acad Sci U S A 102, 17148-17153.

Invited Reviews

1. Zhang L & Su L (2012) HIV-1 immunopathogenesis in humanized mouse models. Cell Mol Immunol 9, 237-244, doi: 10.1038/cmi.2012.7.

2. Zhang L, Meissner E, Chen J & Su L (2010) Current humanized mouse models for studying human immunology and HIV-1 immuno-pathogenesis. Sci China Life Sci 53, 195-203, doi: 10.1007/s11427-010-0059-7 [doi].

（资料来源：张立国研究员，2020-11-12）