The research in my laboratory focuses on the following three areas:
Molecular pathogenesis of chronic hepatitis B virus infection. Persistent infection of hepadnaviruses, represented by hepatitis B virus (HBV), is maintained by the presence of a small and regulated number of covalently closed circular (ccc) DNA in the nuclei of infected hepatocytes. The cccDNA is formed by conversion of viral relaxed circular (rc) and double stranded linear (dsl) DNA from cytoplasmic capsids via unknown mechanisms and exists in the nuclei of infected cells as minichromosome that severs as the transcription template for viral RNAs. We are currently interested in (i) understanding how HBV cccDNA is synthesized, stably maintained and transcriptionally regulated and (ii) identifying host factors that are essential for or restrict HBV replication in hepatocytes.
Innate immunity against virus infection. The goal under this research program is to dissect the molecular basis of the interactions between human pathogenic viruses (HBV, HCV and WNV) and host cellular innate immune defense response. Our current research is toward answering the following three questions: (i) how is innate immune response activated upon virus infection? (ii) How does innate immune response control the replication of the viruses? (iii) How could viruses establish infections in the face of cellular innate defense? The answers to those questions will help us to understand the pathogenesis of those medically important pathogens and develop the therapeutic and preventing means to control their infections and deadly clinical consequences. The current research projects include that (i) identification of IFN-induced cellular proteins that inhibits the replication of HCV, WNV and other flaviviruses; (ii) elucidation of the antiviral mechanism of viperin and ISG20 against HCV; (iii) dissecting the molecular basis of WNV inhibition of interferon signal transduction and (iv) determining the role of PI3K signaling pathway in the viral activation of RIG-I/MDA5-mediated innate immune response.
Discovery of antiviral and host innate immune modulatory agents. We have recently initiated a research program to discover small molecular inhibitors of HBV, HCV, and flavivirus infection. In particular, we have developed a cell-based assay suitable for high throughput screening of compounds that inhibit key steps of HBV replication, such as capsid assembly, pre-genomic RNA packaging, and priming and elongation of viral DNA synthesis. In addition, taking advantage of a cell-based assay system developed in our antiviral innate immunity studies, we are also looking for compounds that modulate TLR3 and RIG-I-mediated innate immune response and compounds that enhance the antiviral response of IFN-alpha against HBV and HCV. The innate immunity modulators discovered in this program could potentially be developed into antiviral agents or molecular probes for dissecting signal transduction pathways of the innate immune response.
Selected Research Publications:
"The innate immune response to hepatitis B virus infection: Implications for pathogenesis and therapy"
Chang J, Block TM, and J-T Guo
Antiviral Research, doi:pii: S0166-3542(12)00231-8. 10.1016/j.antiviral.2012.10.001. [Epub ahead of print], 2012.
"RO 90-7501 Enhances TLR3 and RLR Agonist Induced Antiviral Response"
Guo F, Mead J, Aliya N, Wang L, Cocunati A, Li K, Wei L, Block TM, Guo J-T, and J Chang
PLoS ONE 7(10): e42583, 2012.
"Characterization of the Host Factors required for Hepadnavirus Covalently Closed Circular (ccc) DNA Formation"
Guo H, Xu C, Zhou T, Block TM, and J-T Guo
Plos ONE, 7(8): e43270, 2012.
"Identification of the Disubstituted Sulfonamide Compounds as Specific Inhibitors of Hepatitis B Virus Covalently Closed Circular DNA"
Cai D, Mills C, Yu W, Yan R, Aldrich C, Saputelli J, Mason WS, Xu X, Guo J-T, Block TM, Cuconati A, and H Guo
Antimicrobial Agents and Chemotherapy, 56(8): 4277-4288, 2012.
"Inhibitors of endoplasmic reticulum alpha-glucosidases potently suppress hepatitis C virus virion assembly and release"
Qu X, Pan X-B, Weidner JM, Yu W, Alonzi D, Xu X, Butters T, Block TM, Guo J-T and Chang J
Antimicrobial Agents and Chemotherapy, 55(3): 1036-1044, 2011.
"Indoleamine 2, 3-dioxygenase mediates the antiviral effect of gamma interferon against hepatitis B virus in human hepatocyte-derived cells"
Mao R, Zhang J, Jiang D, Cai D, Levy JM, Cuconati A, Block TM, Guo JT* and Guo H* (* Co-corresponding authors)
Journal of Virology, 95(2): 1048-1057, 2011.
"Antiviral Activities of ISG20 in Positive-strand RNA Virus Infections"
Zhou Z, Wang N, Woodson SE, Dong Q, Wang J, Liang Y, Rijnbrand R, Wei L, Nichols JE, Guo JT, Holbrook MR, Lemon SM and Li K
Virology, 409(2): 175-188, 2011.
"Interferon-induced cell membrane proteins, IFITM3 and tetherin, inhibit vesicular stomatitis virus infection via distinct mechanisms"
Weidner JM, Jiang D, Pan XB, Chang J, Block TM and Guo JT
Journal of Virology, 84(24): 12646-12657, 2010
"Interferons accelerate the decay of replication-competent nucleocapsids of hepatitis B virus"
Xu C, Guo H, Pan XB, Mao R, Yu W, Xu X, Wei L, Chang J, Block TM and Guo JT
Journal of Virology, 84(18): 9332-9340, 2010.
"Identification of five interferon-induced cellular proteins that inhibits West Nile virus and dengue virus infection"
Jiang D, Weidner JM, Qing M, Guo H, Xu C, Zhang X, Birk A, Chang J, Shi PY, Block TM and Guo JT
Journal of Virology, 84(16): 8332-8341, 2010
"Production and function of the cytoplasmic deproteinized relaxed circular DNA of hepadnaviruses"
Guo H, Mao R, Block TM, and Guo JT
Journal of Virology, 84(1): 387-396, 2010.
"Antiviral Effect of Interferon lambda against West Nile Virus"
Ma D, Jiang D, Qing M, Weidner JM, Qu X, Guo H, Chang J, Gu B, Shi PY, Block TM, and Guo JT
Antiviral Research, 83(1): 53-60, 2009.
"Novel Imino Sugar Derivatives Demonstrate Potent Antiviral Activity against Flaviviruses"
Chang J, Wang L, Ma D, Qu X, Guo H, Xu X, Mason PM, Bourne N, Moriarty R, Gu B, Guo JT, and Block TM
Antimicrobial Agents and Chemotherapy, 53(4): 1501-1508, 2009.
"Activation of pattern recognition receptor-mediated innate immunity inhibits the replication of hepatitis B virus in human hepatocyte-derived cells"
Guo H, Jiang D, Ma D, Chang J, Dougherty AM, Cuconati A, Block TM, and Guo JT
Journal of Virology, 83(2): 847-58, 2009.
"Identification of interferon induced cellular proteins that are responsible for the inhibition of hepatitis C virus replication"
Jiang D, Guo H, Xu C, Wang L, Gu B, Block TM, and Guo JT
Journal of Virology, 82(4): 1665-1678, 2008.