MENU

Christoph Seeger, PhD

Christoph Seeger, PhD

Professor

Research Program

Physical map of hepatitis B virus (HBV)
HBV life cycle
Model for CCC DNA synthesis

 

Educational Background

  • Postdoctoral Fellow, University of California-San Francisco, San Francisco, CA
  • PhD, Biocenter, University of Basel, Basel, Switzerland, 1982
  • MS, Biocenter, University of Basel, Basel, Switzerland, 1979

Honors & Awards

  • Fellow, American Association for the Advancement of Science
  • Fellow, American Academy of Microbiology

Research Program

Research Interests

  • DNA repair enzymes involved in hepatitis B virus replication.
  • Development of CRISPR/Cas9 platforms for investigations on HBV life.
  • Use of CRISPR/Cas9 for genome-wide screens to identify drivers of drug resistance in liver cancer therap

Lab Overview

We are interested in the biology of human pathogenic viruses with an emphasis on mechanisms of viral replication and host-virus interactions that play a role in innate immunity. Our investigations on hepatitis B virus (HBV) lead to the identification of the signals required for reverse transcription of the viral DNA and provided the basis for the current model for hepadnavirus replication. We discovered that the hepatitis B polymerase could be expressed in enzymatically active form in the presence of the heat shock protein 90 complex. Moreover, we demonstrated that recovery from chronic hepatitis B infections requires massive destruction of infected hepatocytes. Investigations on hepatitis C virus (HCV) lead to the discovery that HCV replication could occur in cells of non-hepatic origin in human and mouse cells and hence did neither depend on hepatocyte –or primate-specific factors. We demonstrated that IFN resistance observed in patients was not caused by the emergence of IFN-resistant variants, but rather reflected resistance of hepatocytes to induce an effective antiviral program normally induced by IFN. Furthermore, we discovered that, in contrast to HCV, West Nile virus (WNV) could block the IFN response by inhibiting the phosphorylation of the Janus kinases Jak1 and Tyk2.

In line with our interest in HBV biology, the goal of our current research effort is to investigate one of the least understood steps in HBV replication: the mechanism by which the viral genome is converted into a covalently closed circular (ccc) DNA form and how intracellular amplification of cccDNA is regulated. To conduct our studies, we have developed a CRISPR/Cas9 platform permitting HBV infection of cells with specific gene knockouts. In addition, we are exploring a novel strategy to eliminate cccDNA from infected cells with the help of the CRISPR/Cas9 system. Finally, we are using genome-wide CRISPR/Cas9 screening to identify genes that confer sensitivity or resistance to anticancer drugs used in the treamtment of hepatocellular carcinoma.

People

Ji Sohn BS

Technical Specialist

Room: R216
215-728-4313

Pietro Mancuso

Scientific Technician II

Room: R216, 4313

Mingming Li

Student

Room: R216, 4313

Selected Publications

Cui, X., McAllister, R., Boregowda, R., Sohn, J.A., Ledesma, P., Caldecott, K.W., Seeger,C., Hu, J. Does tyrosyl DNA phosphodiesterase-2 play a role in hepatitis B virus genome repair? PLoS ONE 10(6): e012840, 2015. PubMed

Hu, J. and Seeger, C. Hepadnavirus genome replication and persistence. In: Hepatitis B and Delta Viruses (Seeger, C. and Locarnini, S., Eds.). pp 75-90, Cold Spring Harbor Laboratory Press. 2015. PubMed

Seeger, C. and Mason, W.S. Molecular biology of hepatitis B virus infection. Virology 479-480:672, 2015. PubMed

Seeger, C and Sohn J.A. Targeting HBV cccDNA with CRISPR/Cas9. Molecular Therapy-Nucleic Acids, e216; doi:10.1038/mtna.2014.68, 2014. PubMed

Chisari F.V.,Mason, W.S., Seeger, C. Virology. Comment on “Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA”. Science 344:1237, 2014. PubMed

Evans, J.D., Crown, R.A., Sohn, J.A., Seeger, C. West Nile Virus infection induces depletion of IFNAR1 protein levels. Viral Immunology 24:253-263, 2011. PubMed

Sohn, J.A., Litwin, S., Seeger, C. Mechanism for CCC DNA synthesis in hepadnaviruses. PLoS ONE 4(11): e8093, 2009. PubMed