Ju- Tao Guo, MD
W. Thomas London Distinguished Professor at the Blumberg Institute (Principal Investigator)
Ph: (215) 489-4929
(1988) M.S. Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
(1985) M.D. Lanzhou University College of Medicine, Lanzhou, China
(1994) Postdoctoral Fellow, Fox Chase Cancer Center, Philadelphia, PA, U.S.A.
Appointment at the Baruch S. Blumberg Institute: W. Thomas London Distinguished Professor; Chair, Department of Experimental Therapeutics
Other appointments: Adjunct Associate Professor, Department of Microbiology and Immunology, Drexel University College of Medicine (http://www.drexel.edu/medicine/Faculty/Profiles/Ju-Tao-Guo/)
The Guo laboratory research is mainly focused on understanding the pathogenesis of HBV infection and discovering antiviral and immune modulating agents to treat chronic hepatitis B. It also has a long-term research effort toward understanding how interferons control virus infection and how viruses evade innate antiviral immune responses to colonize their hosts.
Hepatitis B virus (HBV) research
Chronic hepatitis B virus (HBV) infection affects more than 240 million people worldwide. Although there are 7 medications have been approved by US FDA for treatment of chronic hepatitis B and they are efficacious in suppressing HBV replication, reducing viral load and improving clinical manifestations, they rarely induce a sustained, off-drug control of HBV replication, HBsAg loss or seroconversion (a functional cure). The reasons are those medications, particularly HBV DNA polymerase inhibitors, fail to eliminate (or repress) cccDNA and restore a functional antiviral immune response against HBV. Accordingly, our HBV research program is to understand the molecular basis of cccDNA metabolism, transcription regulation and their modulation by host immune responses. The Guo lab’s ultimate goals are to therapeutically eliminate/repress cccDNA and restore an effective host immune response against HBV to cure the chronic HBV infection.
Molecular pathogenesis of chronic HBV infection One of the major remaining mysteries about the pathogenesis of HBV is how the host immune system resolves the virus infection and eliminates the nuclear form of the viral genome, the covalently closed circular (ccc) DNA. Following entry of HBV into hepatocytes, the viral relaxed circular (rc) DNA genome is transported into the nucleus and converted into cccDNA with the help of cellular DNA repair machinery. CCC DNA associates with histones and assembles into episomal minichromosome, which is the transcriptional template for viral mRNA. Persistent HBV infection relies on stable maintenance and proper functioning of cccDNA. Thus, resolution of infection depends upon elimination and/or transcriptional suppression of cccDNA. The Guo lab’s current research is to investigate the molecular mechanism of cccDNA biosynthesis, maintenance, transcription regulation and their regulation by host innate immune response, particularly, interferons and other inflammatory cytokines.
Innate immunity against HBV infection HBV was considered a stealth virus that induces negligible innate immune responses during the early phase of infection. However, recent studies with newly developed experimental systems revealed that the virus infection can be recognized, at least under selected conditions, by pattern recognition receptors, and elicits a cytokine response that controls the replication of the virus. In addition, it has also been shown that the functional status of intrahepatic innate immunity determines the activation and maturation of HBV-specific adaptive immune response and thus the outcomes of HBV infection. Encouragingly, pharmacological activation of intrahepatic innate immune response with TLR7/8/9 or STING agonists efficiently controls HBV infection in preclinical studies and thus holds great promise for the cure of chronic hepatitis B. Accordingly, our current research is to investigate under what the condition and how cGAS-STING pathway recognizes HBV infection and determine the molecular mechanism by which STING agonist-induced antiviral response controls HBV replication.
Discovery and development of antiviral and host innate immunity modulating agents for treatment of chronic hepatitis B As an extension of our basic research projects on HBV pathogenesis and innate immunity, we have also developed cell-based assays suitable for high throughput screening of antiviral agents and innate immunity agonists to treat chronic HBV infection. Specifically, our antiviral agent discovery and development program focuses on discovering small molecular inhibitors of HBV replication, particularly to target the steps of capsid assembly, pgRNA encapsidation, viral DNA synthesis, cccDNA formation, maintenance and transcription of viral RNA. Two chemically distinct classes of HBV nucleocapsid assembly inhibitors have been discovered and are currently under preclinical development. The Guo lab is also discovering human STING agonists in collaboration with Drs. Jinhong Chang and Yanming Du.
Innate antiviral immunity
Interferons (IFN) are the primary mediators of host innate and adaptive antiviral immune responses. Taking a forward genetic approach, the laboratory has identified interferon stimulated genes (ISGs) that suppress the infection of HBV, HCV, flaviviruses and human coronaviruses during the last decade. We are now particularly interested in understanding the antiviral mechanism of three membrane-associated ISGs, viperin, tetherin and IFITMs. While viperin inhibits RNA replication of HCV and flaviviruses, tetherin and IFITMs inhibit a broad-spectrum of viruses by disrupting their egress from infected cells and entry into their host cells, respectively. Intriguingly, we also found that at least one virus, human coronavirus OC43 (HCoV-OC43), can use IFITM proteins to facilitate its entry into host cells, most likely by promoting the fusion between viral envelope and endosomal membranes. Further genetic and biochemical studies are currently under way to investigate the mechanisms by which those antiviral ISGs, particularly the IFITM proteins, modulate virus infection.
Innate host defense systems and viral infections, with an emphasis on hepatitis B viruses.
Xiuji Cui, Daniel Clark, Kuancheng Liu, Xiao-Dong Xu, Ju-Tao Guo, and Jianming Hu (2015) Viral DNA-dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes. Journal of Virology. 2015 Oct 21. pii: JVI.01263-15. [Epub ahead of print]
Jake Liang , Timothy M. Block, Brian J. McMahon , Marc G. Ghany, Stephan Urban, Ju-Tao Guo, Stephen Locarnini, Fabien Zoulim, Kyong-Mi Chang, Anna S. Lok (2015) Present and Future Therapies of Hepatitis B: From Discovery to Cure. Hepatology. 2015 Aug 3. doi: 10.1002/hep.28025. [Epub ahead of print]
Ju-Tao Guo and Haitao Guo (2015) Metabolism and Function of HBV cccDNA: Implications for Development of cccDNA-Targeting Antiviral Therapeutics. Antiviral Research, 122:91-100.
Jinhong Chang and Ju-Tao Guo (2015) Treatment of chronic hepatitis B with pattern recognition receptor agonists: Current status and potential for a cure. Antiviral Research. 121:152-159.
Ran Yan, Xuesen Zhao, Dawei Cai, Yuanjie Liu, Tim Block, Ju-Tao Guo, Haitao Guo(2015). Interferon-induced protein BST-2/Tetherin Inhibits Hepatitis B Virus Particle Secretion. Journal of Virology. 89(18):9200-12.
Xiuji Cui, Ju-Tao Guo, and Jianming Hu. (2015) Hepatitis B Virus Covalently Closed Circular DNA Formation in Immortalized Mouse Hepatocytes Associated with Nucleocapsid Destabilization, Journal of Virology. 2015 89(17):9021-8. (Covered by JVI Spotlight).
Wenhui He, Bijie Ren, Zhiyi Jing, Fengfeng Mao, Yang Liu, Bo Peng, HuanYan, Yonghe Qi, Yinyan Sun, Ju-Tao Guo, Jianhua Sui, Fengchao Wang, Wenhui Li. (2015) Hepatitis D virus infection of mice expressing human sodium taurocholate co-transporting polypeptide. PLoS Pathogens. 11(4):e1004840 (commented in Nature Reviews Gastroenterology & Hepatology advance online publication 12 May 2015; doi:10.1038/nrgastro.2015.76).
Fang Guo, Yanxing Han, Xuesen Zhao, Jianghua Wang, Fei Liu, Chunxiao Xu, Lai Wei, Jian-Dong Jiang, Timothy M. Block, Ju-Tao Guo and Jinhong Chang (2015). STING agonists induce a potent innate antiviral immune response against hepatitis B virus. Antimicrob Agents Chemother. 59(2):1273-81.
Xuesen Zhao, Fang Guo, Mary Ann Comunale, Anand Mehta, Mohit Sehgal, Pooja Jain, Andrea Cuconati, Hanxin Lin, Timothy M. Block, Jinhong Chang and Ju-Tao Guo (2015) Inhibition of ER glucosidases impairs SARS-CoV and HCoV-NL63 spike protein-mediated entry by altering the glycan processing of ACE2. Antimicrob Agents Chemother. 59(1):206-16.
Jinhong Chang, Timothy M. Block and Ju-Tao Guo (2015) Viral resistance of MOGS-CDG patients implies a broad-spectrum strategy against acute virus infections. Antiviral Therapy. 20(3):257-9.
Jinhong Chang, Fang Guo, Xuesen Zhao and Ju-Tao Guo(2014) Therapeutic strategies for a functional cure of chronic hepatitis B virus infection. Acta Pharmaceutica Sinica B. 4(4):248–257 (Highlighted as cover story).
Fang Guo, Xuesen Zhao, Tina Gill, Yan Zhou, Matthew Campagna, Lijuan Wang, Fei Liu, Pinghu Zhang, Laura DiPaolo, Yanming Du, Xiaodong Xu, Dong Jiang, Lai Wei, Andrea Cuconati, Timothy M. Block, Ju-Tao Guo and Jinhong Chang (2014) An interferon-beta promoter reporter assay for high throughput identification of compounds against multiple RNA viruses. Antiviral Res. 107:56-65.
Xuesen Zhao, Fang Guo, Fei Liu, Andrea Cuconati, Jinhong Chang, Timothy M. Block and Ju-Tao Guo. (2014) Interferon induction of IFITM proteins promotes infection by human coronavirus OC43. Proc Natl Acad Sci U S A. 111(18):6756-6761.
Arun Upadhyay, Kirstin Vonderstein, Andreas Pichlmair, Oliver Stehling, Keiryn Bennett, Gerhard Dobler, Ju-Tao Guo, Giulio Superti-Furga, Roland Lill, Anna Överby, Friedemann Weber (2014). Viperin is an iron-sulfur protein that inhibits genome synthesis of tick-borne encephalitis virus via radical SAM domain activity. Cellular Microbiology, 16(6), 834–848.
Xiaoming Chen, Bangyao Dai, Zhengcai Liu, Jie Gao, Zhaohua Ji, Ju-Tao Guo, Gang Chen, Zhongrong Deng, and Zhongjun Shao (2014). A novel B/C inter-genotype recombinant of hepatitis B virus identified in China. Journal of General Virology. 95 Pt 1:153-5.
Jinhong Chang, Ju-Tao Guo, Yanming Du and Timothy Block (2013). Imino sugar glucosidase inhibitors as broadly active anti-filovirus agents. Emerging Microbes and Infections. e77; doi:10.1038/emi.2013.77.
Fei Liu, Matthew Campagna, Yonghe Qi, Xuesen Zhao, Fang Guo, Chunxiao Xu, Sichen Li, Wenhui Li, Timothy M. Block, Jinhong Chang, and Ju-Tao Guo. (2013) Alpha-Interferon Suppresses Hepadnavirus Transcription by Altering Epigenetic Modification of cccDNA Minichromosomes. PLoS Pathogens, 9(9): e1003613.
Dawei Cai, Hui Nie, Ran Yan, Ju-Tao Guo, Timothy M. Block, Haitao Guo (2013) A SouthernBlot Assay for Detection of Hepatitis B Virus Covalently Closed Circular DNA from Cell Cultures. Methods Mol Biol. 2013;1030:151-161.
Shijian Zhang, Ju-Tao Guo, Jim Wu, and Guang Yang (2013) Identification and characterization of multiple TRIM proteins that inhibit hepatitis B virus transcription. PLoS ONE, 8(8): e70001.
Jinhong Chang, Timothy M. Block and Ju-Tao Guo (2013) Host ER alpha-glucosidase-targeted antiviral therapy: Current status and future directions. Antiviral Research, 99(3):251-260.
Richeng Mao, Hui Nie, Dawei Cai, Jiming Zhang, Hongyan Liu, Ran Yan, Andrea Cuconati, Timothy M. Block, Ju-Tao Guo, Haitao Guo (2013) Inhibition of Hepatitis B Virus Replication by the Host Zinc Finger Antiviral Protein. PLoS Pathogens, 9(7):e1003494.
Yanming Du, Hong Ye, Fang Guo, Lijuan Wang, Tina Gill, Noshena Khan,Andrea Cuconati, Ju-Tao Guo, Timothy M. Block, Jinhong Chang, Xiaodong Xu. (2013) Design and synthesis of N-alkyldeoxynojirimycin derivatives with improved metabolic stability as inhibitors of BVDV and Tacaribe virus. Bioorganic & Medicinal Chemistry Letters. 23(14):4258-62.
Matthew R. Campagna, Fei Liu, Richeng Mao, Courtney Mills, Dawei Cai, Fang Guo, Xuesen Zhao, Hong Ye, Andrea Cuconati, Haitao Guo, Jinhong Chang, Xiaodong Xu, Timothy M. Block and Ju-Tao Guo (2013) Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids. J. Virol. 87(12):6931-42.
Jinhong Chang, Travis K. Warren, Xuesen Zhao, Tina Gill, Lijuan Wang, Mary Ann Comunale, Yanming Du, Wenquan Yu, Hong Ye, Fang Guo, Fei Liu, Ju-Tao Guo, Anand Mehta, Andrea Cuconati, Terry Butters, Sina Bavari, Xiaodong Xu, Timothy M. Block (2013) Small molecule inhibitors of ER α-glucosidases are active against multiple hemorrhagic fever viruses. Antiviral Research. 2013 98(3):432-40.
Timothy M. Block, Robert Gish, Haitao Guo, Anand Mehta, Andrea Cuconati, W. Thomas London and Ju-Tao Guo. (2013) Chronic hepatitis B: What should be the goal for new therapies? Antiviral Research. 98(1):27-34.
Yanming Du, Hong Ye, Tina Gill, Lijuan Wang, Fang Guo, Andrea Cuconati, Ju-Tao Guo, Timothy M. Block, Jinhong Chang, Xiaodong Xu. (2013) N-Alkyldeoxynojirimycin derivatives with novel terminal tertiary amide substitution for treatment of bovine viral diarrhea virus (BVDV), Dengue, and Tarcaribe virus infections. Bioorganic & Medicinal Chemistry Letters. 23(7):2172-6.