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微生物与传染病学

张敬仁

​清华大学亚博全站手机网页登录教授

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探索病原菌致病分子机制,研发疾病新型干预策略

张敬仁教授1997年获美国得克萨斯大学医学中心博士学位,并于1997年进入美国圣祖德儿童医院研究所从事博士后研究工作。2000年至2010年,于美国阿尔巴尼亚博全站手机网页登录任助理教授、副教授。2010年回国至今于清华大学任亚博全站手机网页登录长聘教授。曾荣获美国微生物学会Raymond W. Sarber奖、美国德克萨斯大学Chancellor’s Entrepreneurship and Innovation Award in Category II、中国国家自然科学基金杰出青年B类基金等。 张敬仁教授团队主要致力于急性细菌性肺炎及败血症病原菌遗传、表观遗传、与宿主相互作用的机制、疫苗保护机制的研究及新型蛋白疫苗的研发,旨为急性细菌感染性疾病的精准诊断、治疗和预防提供新的分子靶标及策略。研究结果于《Cell》、《Nucleic Acids Research》、《PLoS Pathogens》等国际著名杂志发表,并多次入选中国高被引学者。团队通过反向疫苗学策略还发现了多个具有免疫保护效果的肺炎链球菌蛋白抗原,相关成果已获得中国和美国的专利保护。

通过反向疫苗学策略研发普适性肺炎链球菌蛋白疫苗

张敬仁教授团队主要致力于急性感染性疾病病原菌遗传、致病机制、疫苗保护机制的研究及新型蛋白疫苗的研发。研究的病原体主要包括:肺炎链球菌、肺炎克雷伯菌、大肠埃希菌、土拉杆菌、金黄色葡萄球菌等。围绕的主要科学问题包括:1)病原菌依赖哪些自身的基因及其相关功能来达到逃逸宿主天然免疫监控的目的;2)人体的哪些免疫细胞和免疫分子在清除非致病菌中发挥作用,却容忍致病菌的生存与繁殖;3)疫苗免疫如何帮助机体清除原本不能清除的致病菌。解决这些重大科学问题将为急性细菌感染性疾病的精准诊断、治疗和预防提供新的分子靶标及策略。

·细菌感染性疾病新型干预策略相关研究

张敬仁教授团队通过反向疫苗学策略,鉴定出多个具有免疫保护性的肺炎链球菌蛋白抗原,相关结果已获得中国和美国专利保护;他还与国内外药物化学家合作发现针对肺炎克雷伯菌、大肠埃希菌和肺炎链球菌等病原菌耐药株的先导化合物。

·病原菌致病机制相关研究

张敬仁教授团队发现并阐明了肺炎链球菌调控其致病性的表观遗传机制;发现了人与动物“莱姆病”的蛋白抗原VlsE,并被广泛用于疾病的快速诊断;发现了人呼吸道上皮细胞识别肺炎链球菌 CbpA 蛋白的受体——pIgR;揭示了肺炎链球菌调控荚膜合成的分子机制;系统筛查并发现了一批肺炎链球菌和土拉杆菌的新型致病因子。

·彰显中国在肺炎链球菌研究领域的国际影响力

张敬仁教授近五年共发表SCI 论文二十余篇,多年来一直被列为中国微生物学与免疫学高被引学者。多次被邀请为国家微生物学权威专著撰写章节。多次被邀请在国际知名大学和相关国际会议作学术报告。其中包括2018年11月在韩国首尔举行的“中日韩肺炎链球菌学术研讨会”和2019年6月在德国格赖夫斯瓦尔德举行的“第14次欧洲肺炎链球菌学术论坛”等重要国际会议。担任多个国内外微生物学相关杂志的编委和编辑。被聘任为国内多家上市药企的科学顾问。2019年10月负责举办我国第一个以肺炎链球菌为主题的国际学术会议“第二届亚洲肺炎链球菌学术论坛”。这是我国有史以来第一次举办以肺炎链球菌为主题的国际学术会议,彰显了中国在这个重要领域的国际影响力。

1.Huang, Xueting, Xiuyuan Li, Haoran, Juanjuan Wang, Ming Ding, Lijun Wang, Lulu Li, Quanjiang Ji, Fen Qu, Hui Wang, Yingchun Xu, Xinxin Lu and Jing-Ren Zhang*. Capsule type defines the capacity of Klebsiella pneumoniae in evading Kupffer cell capture in the liver. PLOS Pathogens. In press.

2.Guo, Ziyi, Haoqi Yang, Jing-Ren Zhang, Wenwen Zeng, and Xiaoyu Hu. Leptin receptor signaling sustains metabolic fitness of alveolar macrophages to attenuate pulmonary inflammation. Science Advances. In press.

3.Haoran An, Chenyun Qian, Yijia Huang, Jing Li, Xianbin Tian, Jiaying Feng, Jiao Hu, Yujie Fang, Fangfang Jiao, Yuna Zeng, Xueting Huang, Xianbin Meng, Xue Liu, Xin Lin, Zhutian Zeng, Martin Guilliams, Alain Beschin, Yongwen Chen, Yuzhang Wu, Jing Wang, Marco R. Oggioni, John M. Leong, Jan-Willem Veening, Haiteng Deng, Rong Zhang, Hui Wang, Jiang Wu, Yan Cui, and Jing-Ren Zhang*. 2022. Functional vulnerability of liver macrophages to capsules defines virulence of blood-borne bacteria. Journal of Experimental Medicine 219:e20212032. DOI:10.1084/jem.20212032.

4.Menglan Zhou, Ziran Wang, Li Zhang, Timothy Kudinha, Haoran An, Chenyun Qian, Jiang Bin, Yao Wang, Ying-Chun Xu, Zhengyin Liu*, Hong Zhang* and Jing-Ren Zhang*. 2022. Serotype distribution, antimicrobial susceptibility, multilocus sequencing type and virulence of invasive Streptococcus pneumoniae in China: a six-year multi-center study. Frontiers in Microbiology 12:798750. DOI:10.3389/fmicb.2021.798750.

5.Qingqing Hu, Huichun Tong, Jing Wang, Pupu Ge, Lin Zhu, Cuihua Liu, Jing-Ren Zhang, Xiuzhu Dong. 2021. A novel aquaporin subfamily imports oxygen and contributes to pneumococcal virulence by controlling production and release of virulence factors. mBio 12:e01309-21. https://doi.org/10.1128/mBio.01309-21.

6.Zhang, Chengwang, Haoran An, Jiao Hu, Jing Li, Wenhao Zhang, Xun Lan, Haiteng Deng, and Jing-Ren Zhang*. 2021. MetR is a molecular adaptor for pneumococcal carriage in the healthy upper airway.  Molecular Microbiology 116:438-458. DOI:10.1111/MMI.14724.

7.Huang, Xueting, Juanjuan Wang, Jing Li, Yanni Liu, Xue Liu, Zeyao Li, Kurni Kurniyati, Yijie Deng, Guilin Wang, Joseph D. Ralph, Megan De Ste Croix, Sara Escobar-Gonzalez, Richard J. Roberts, Jan-Willem Veening, Xun Lan, Marco R. Oggioni*, Chunhao Li*, and Jing-Ren Zhang*. 2020. Prevalence of phase variable epigenetic invertons among host-associated bacteria. Nucleic Acids Research 48:11468-11485.  DOI:10.1093/nar/gkaa907.

8.Wang, Juanjuan, Jing-Wen Li, Yijia Huang, Shaolin Wang, and Jing-Ren Zhang*. 2020. Regulation of pneumococcal epigenetic and colony phases by multiple two-component regulatory systems. PLOS Pathogens 16 (3):e1008417. DOI:10.1371/journal.ppat.1008417.

9.Li, Jing.-Wen, Juanjuan Wang, Sofia Ruiz-Cruz, Manuel Espinosa, Jing-Ren Zhang*, and Alicia Bravo*. 2020. In vitro DNA inversions mediated by the PsrA site-specific tyrosine recombinase of Streptococcus pneumoniae. Frontiers in Molecular Biosciences 7:43. DOI:10.3389/fmolb.2020.00043.

10.Li, Jing-Wen, Jing Li, Juanjuan Wang, Chunhao Li, and Jing-Ren Zhang*. 2019. Molecular mechanisms of hsdS inversions in the cod locus of streptococcus pneumoniae. Journal of Bacteriology 201(6):e00581-18. DOI:10.1128/JB.00581-18.  Chosen by the editor as the Article of Significant Interest in This Issue, DOI:10.1128/JB.00023-19.

11.Liu, Yanni, Yuna Zeng, Yijia Huang, Gu L, Shaolin Wang, Chunhao Li, Donald A. Morrison, Haiteng Deng*, Jing-Ren Zhang*. 2019. HtrA‐mediated selective degradation of DNA uptake apparatus accelerates termination of pneumococcal transformation. Molecular Microbiology 112:1308-1325. DOI:10.1111/mmi.14364.

12.Li, Jing and Jing-Ren Zhang*. 2019. Phase variation of Streptococcus pneumoniae. Microbiology Spectrum 7(1). DOI:10.1128/microbiolspec.GPP3-0005-2018.

13.Zong, Yu, Fang Fang, Kirsten J. Meyer, Liguo Wang, Zhihao Ni, Hongying Gao. Kim Lewis, Jing-Ren Zhang, and Yu Rao. 2019. Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics. Nature Communications 10:3268. DOI:10.1038/s41467-019-11211-y.

14.Zhang, Kai, Zhuan Qin, Yunjie Chang, Jun Liu, Michael G. Malkowski, Saimtun Shipa, Li Li, Weigang Qiu, Jing-Ren Zhang, and Chunhao Li*. 2019. Analysis of a flagellar filament cap mutant reveals that HtrA serine protease degrades unfolded flagellin protein in the periplasm of Borrelia burgdorferi.  Molecular Microbiology 111:1652-1670. DOI:10.1111/mmi.14243.

15.Wang, Xu, Yuna Zeng, Li Sheng, Peter Larson, Xue Liu, Xiaowen Zou, Shufang Wang, Kaijing Guo, Chen Ma, Gang Zhang, Huaqing Cui, David Ferguson, Yan Li, Jing-Ren Zhang*, and Courtney Aldrich*. 2019.  A cinchona alkaloid antibiotic that appears to target ATP synthase in Streptococcus pneumoniae. Journal of Medicinal Chemistry 62:2305-2332. DOI:10.1021/acs.jmedchem.8b01353.

16.Wang, Yang, Zhensong Wen, Xiaolei Pan, David E. Briles, Yongqun He, and Jing-Ren Zhang*. 2018. Novel immunoprotective proteins of Streptococcus pneumoniae identified by opsonophagocytosis killing screen. Infection and Immunity 86(9):e00423-18. DOI: 10.1128/IAI.00423-18.

17.He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, and Jing-Ren Zhang*. 2018. Multiple domains of bacterial and human Lon proteases define substrate selectivity. Emerging Microbes and Infections (2018):149. DOI:10.1038/s41426-018-0148-4.

18.Kurniyati, Kurni, Jun Liu, Jing-Ren Zhang, Yunjiang Min, and Chunhao Li*. 2018. A pleiotropic role of FlaG homolog in regulating the cell morphogenesis and flagellar homeostasis at the cell poles of Treponema denticola. Cellular Microbiology 21:e12886. DOI:10.1111/cmi.12886.

19.Pan, Yushan *, Haoran An, Tong Fu, Shiyu Zhao, Chengwang Zhang, Genhui Xiao, Jing-Ren Zhang, Xinfang Zhao, Gongzheng Hu*. 2018. Characterization of Streptococcus pluranimalium from a cattle with mastitis by whole genome sequencing and functional validation. BMC Microbiology 18:182.  DOI:10.1186/s12866-018-1327-0

20.Xu, Miao, Huiping Lu, Young-Hee Lee, Y. Wu, Kewei Liu, Yuling Shi, Haoran An, Jing-Ren Zhang, Xiaohu Wang, Yuping Lai, and Chen Dong*. 2018. An Interleukin-25-mediated autoregulatory circuit in keratinocytes plays a pivotal role in psoriatic skin inflammation. Immunity 48:787-798 e4. DOI:10.1016/j.immuni.2018.03.019.

21.Liu, Xue, Jing-Wen Li, Zhixin Feng, Yongfu Luo, Jan-Willem Veening, and Jing-Ren Zhang*. 2017. Transcriptional repressor PvtR regulates phenotypic tolerance to vancomycin in Streptococcus pneumoniae. Journal of Bacteriology 199(14). pii:e00054-17. DOI:10.1128/JB.00054-17.

22.Li, Jing, Juanjuan Wang, Fangfang Jiao and Jing-Ren Zhang*. 2017. Observation of pneumococcal phase variation in colony morphology. Bio-protocol 7:Iss15. DOI:10.21769/BioProtoc.2434.

23.Yu, Yuanyuan, Jing-Wen Li, Long Jiang, Jing-Ren Zhang*, and Liansuo Zu*. 2017. Catalytic enantioselective aza-pinacol rearrangement. Angewandte Chemie International Edition English 56:9217-9221. DOI:10.1002/anie.201705539.

24.Chen, Fei, Guolin Cui, Shuxia Wang, Manoj K. Mohan Nair, Lihong He, Xinyi Qi, Xiangmin Han, Hanqi Zhang, Jing-Ren Zhang*, and Jingliang Su*.  2017. Outer membrane vesicle-associated lipase FtlA enhances cellular invasion and virulence in Francisella tularensis LVS. Emerging Microbes and Infections 6:e66. DOI:10.1038/emi.2017.53.

25.Liu, Bo, Xue Liu, Jing-Ren Zhang*, and Gang Liu*. 2017. A natural lipotrisaccharide and its derivatives selectively lyse Streptococcus pneumoniae via interaction with cell membrane.  ACS Infectious Diseases 3:438-453. DOI:10.1021/acsinfecdis.7b00008.

26.Liu, Xue, Clement Gallay, Morten Kjos, Amau Domenech, Jelle Slager, Sebastiaan P. van Kessel, Kevin Knoops, Robin A. Sorg, Jing-Ren Zhang, and Jan-Willem Veening*. 2017. High-throughput CRISPRi phenotyping in Streptococcus pneumoniae identifies new essential genes involved in cell wall synthesis and competence development. Molecular Systems Biology 13:931. DOI:10.15252/msb.20167449.

27.Li, Jing Jing-Wen Li, Zhixin Feng, Juanjuan Wang, Haoran An, Yanni Liu, Yang Wang, Kailing Wang, Xuegong Zhang, Zhun Miao, Wenbo Liang, Robert Sebra, Guiling Wang, Wen-Ching Wang, and Jing-Ren Zhang*. 2016. Epigenetic switch driven by DNA inversions dictates phase variation in Streptococcus pneumoniae. PLOS Pathogens 12: e1005762. DOI:10.1371/journal.ppat.1005762. Highlighted in Nature Reviews Microbiology DOI:10.1038/nrmicro.2016.122.

28.Wen, Zhensong, Yanni Liu, Fen Qu, and Jing-Ren Zhang*. 2016. Allelic variation of the capsule promoter diversifies encapsulation and virulence in Streptococcus pneumoniae. Scientific Reports 6:30176. DOI: 10.1038/srep30176.

29.Li, Guilin, Zhuowen. Liang, Xiatai Wang, Yonghong Yang, Zhujun Shao, Ma Li, Yueyun Ma, Fen Qu, Donald A. Morrison, and Jing-Ren Zhang*. 2016. Addiction of hyper-transformable pneumococcal isolates to natural transformation for in vivo fitness and virulence. Infection and Immunity 84:1887-1901. DOI:10.1128/IAI.00097-16.

30.He, Lihong, Manoj K. Mohan Nair, Yuling Chen, Xue Liu, Mengyun Zhang, Karsten R. O. Hazlett, Haiteng Deng*, and Jing-Ren Zhang*.  2016. The protease locus of Francisella tularensis LVS is required for stress tolerance and infection of mammalian host. Infection and Immunity 84:1387-402. DOI:10.1128/IAI.00076-16.

31.Bai, Xiao-Hui, Qiong Li, Yong-Liang Jiang, Jing-Ren Zhang*, Yuxin Chen*, and Cong-Zhao Zhou*. 2016. Structural comparison and simulation of pneumococcal peptidoglycan hydrolase LytB.  Methods in Molecular Biology. 1440:271-83. DOI:10.1007/978-1-4939-3676-2_19.

32.Yang, Hongzhi, Xue Liu, Qingong Li, Longbo Li, Jing-Ren Zhang*,  and Yefeng Tang*. 2016. Total synthesis and preliminary SAR study of (+/-)-merochlorins A and B. Organic & Biomolecular Chemistry. 14:198-205. DOI: 10.1039/c5ob01946j.

33.Yang, Tao, Gong Chen, Zitai Sang, Yuanyuan Liu, Xiaoyan Yang, Ying Chang, Haiyue Long, Wei Ang, Jianying Tang, Zhenling Wang*, Guobo Li, Shengyong Yang, Jing-Ren Zhang, Yuquan Wei, and Youfu Luo*. 2015. Discovery of a teraryl oxazolidinone compound (S)-N-((3-(3-fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxooxazolidin-5 -yl)methyl)acetamide phosphate as a novel antimicrobial agent with enhanced safety profile and efficacies. Journal of Medical Chemistry 58:6389-409. DOI: 10.1021/acs.jmedchem.5b00152.

34.Wang, Lei, Yong-Liang Jiang, Jing-Ren Zhang, Cong-Zhao Zhou, and Yuxin Chen*. 2015. Structural and enzymatic characterization of the choline kinase LicA from Streptococcus pneumoniae. PLoS One 10:e0120467. DOI:10.1371/journal.pone.0120467.

35.Wen, Zhensong, Odeniel Sertil, Yongxin Chen, Shanshan Zhang, Xue Liu, Wen-Ching Wang, and Jing-Ren Zhang*.  2015. The sequence elements upstream of the core promoter are necessary for the full transcription of the capsule gene operon in Streptococcus pneumoniae strain D39. Infection and Immunity 83:1957-1972. DOI:10.1128/IAI.02944-14.

36.Achila, David, Aizhou Liu, Rahui Banerjee, Yue Li, Erik Martinez-Hackert, Jing-Ren Zhang*, and Honggao Yan*. 2015. Structural determinants of host specificity of complement factor H recruitment by Streptococcus pneumoniae. Biochemical Journal 465:325-335. DOI:10.1042/BJ20141069.

37.Feng, Zhixin., Jing Li, Jing-Ren Zhang*, and Xuegong Zhang*. 2014. qDNAmod: a statistical model based tool to reveal intercellular heterogeneity of DNA modification from SMRT sequencing data. Nucleic Acids Research 42:13488-13499. DOI:10.1093/nar/gku1097.

38.Zhu, Deyu, Lijun Wang, Guijun Shang, Xue Liu, Jing Zhu, Defen Lu, Lei Wang, Biao Kan, Jing-Ren Zhang, and Ye Xiang. 2014. Structural biochemistry of a Vibrio cholerae dinucleotide cyclase reveals cyclase activity regulation by folates. Molecular Cell 55:931-937. DOI:10.1016/j.molcel.2014.08.001.

39.Zeng Xian-Fei, Yueyun Ma, Liu Yang, Lei Zhou, Yijun Xin, Liang Chang, Jing-Ren Zhang, and Xiaoke Hao*. 2014. A C-terminal truncated mutation of licC attenuates the virulence of Streptococcus pneumoniae. Research in Microbiololgy 165: 630-638. DOI:10.1016/j.resmic.2014.09.002.

40.Song, Yongxiang, Qinglian Li, Xue Liu, Yuchan Chen, Yun Zhang, Aijun Sun, Weimin Zhang, Jing-Ren Zhang, and Jianhua Ju*. 2014. Cyclic hexapeptides from the deep South China Sea-derived Streptomyces scopuliridis SCSIO ZJ46 active against pathogenic Gram-positive bacteria. Journal of Natural Products 77:1937-1941. DOI:10.1021/np500399v.

41.Yang, Yi-Hu, Yong-Liang Jiang, Juan Zhang, Lei Wang, Xiao-Hui Bai, Shi-Jie Zhang, Yan-Min Ren, Na Li, Yonghui Zhang, Zhiyong Zhang, Qingguo Gong, Yide Mei, Ting Xue, Jing-Ren Zhang, Yuxin Chen*, and Cong-Zhao Zhou*. 2014. Structural insights into SraP-mediated Staphylococcus aureus adhesion to host cells. PLOS Pathogens 10:e1004169. DOI:10.1371/journal.ppat.1004169.

42.Pan, Xiaolei, Yang Yang, and Jing-Ren Zhang*.  2014. Molecular basis of host specificity in human pathogenic bacteria. Emerging Microbes and Infections 3:e23. DOI:10.1038/emi.2014.23.

43.Gupta, R., Jun Yang, Y. Dong, E. Swiatlo, Jing-Ren Zhang, Dennis W. Metzger, and Guangchun Bai*. 2013. Deletion of arcD in Streptococcus pneumoniae D39 impairs its capsule and attenuates virulence. Infection and Immunity 81:3903-3911.

44.Qaidi, Samir E., Jun Yang, Jing-Ren Zhang, Dennis W. Metzger, and Guangchun Bai*. 2013. The vitamin B6 biosynthesis pathway in Streptococcus pneumoniae is controlled by pyridoxal 5’-phosphate and the transcription factor PdxR, and impacts on ear infection. Journal of Bacteriology 195:2187-2196.


学术荣誉与奖励

2008荣获中国国家自然科学基金海外或港、澳青年学者合作研究基金(杰出青年B类);

2007荣获美国德克萨斯大学系统Chancellor’s Entrepreneurship and Innovation Award in Category II;

1997荣获美国微生物学会The Raymond W. Sarber Award;

1997荣获美国德克萨斯大学休斯敦分校The Presidential Fellowship Award。



开设课程

医学微生物学(清华大学精品课程)

高级微生物学

病原宿主互作

微生物学

生物工程前沿


其他社会职务

1.《Frontiers in Microbiology》杂志,副编辑;

2.《Emerging Microbes and Infection》,编辑;

3.《Journal of Clinical Microbiology》编委;

4.中国自然科学基金、美国NIH研究基金、英国MRC研究基金评审专家;

5.中华预防医学会感染性疾病防控分会,委员;

6.中国微生物协会分析微生物学分会,副理事;

7.康希诺生物股份公司科学顾问委员会顾问。


技术专利

1.专利名称:肺炎链球菌疫苗

专利号:201710084202.2

发明人:张敬仁,王扬,文镇宋,

中国授权日期:2020-05-08

2.专利名称:STREPTOCOCCUS PNEUMONIAE VACCINE

专利号:16/542,497

美国授权日期:2021-05-18