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Our laboratory investigates the molecular relationships between hosts and their pathogens. Specifically, we are investigating the interaction of the innate immune system with the hepatitis C virus (HCV) and West Nile virus (WNV). HCV is a human pathogen of worldwide significance because almost 200 million people are infected with this virus and are at risk for severe liver disease and liver cancer. WNV infects migratory and other birds, which produce high virus titers in their blood, permitting the transmission of the virus to mosquitoes and eventually to humans where it can cause neurological disorders including meningo-encephalitis. Both viruses belong to the Flaviviridae family of viruses. They are enveloped and carry infectious, positive strand RNA genomes of about 10,000 nucleotides in length. Despite their similarities, HCV and WNV evolved diverse strategies to engage host defense mechanisms designed to inhibit viral replication, such as the interferon response, a major arm of the innate immune system. This response is activated when cells “sense” a pathogen resulting in the expression and secretion of the cytokine beta interferon (IFN-β) and the induction of many genes, which alter cellular physiology and thereby reduce amplification and spread of viral pathogens. Results from our laboratory demonstrated that WNV inhibits the signal transduction pathway normally activated by IFN-β. Curiously, HCV does not share this property with WNV. Although the reason for this difference is not known, it might reflect the differences in tissue tropism of the two viruses: HCV is a blood borne pathogen that primarily replicates in hepatocytes of the liver. In contrast, WNV exhibits broad tissue specificity and spreads through the lymphatics, locales known to harbor cells that produce large amounts of IFN.

1. Evans JD, Crown RA, Sohn JA, Seeger C. West Nile Virus infection induces depletion of IFNAR1 protein levels. Viral Immunol. 2011;24:253-263. PubMed
2. Sohn JA, Litwin S, Seeger C. Mechanism for CCC DNA synthesis in hepadnaviruses. PLoS ONE. 2009;4:e8093. PubMed
3. Stiffler JD, Nguyen M, Sohn JA, Liu C, Kaplan D, Seeger C. Focal distribution of hepatitis C virus RNA in infected livers. PLoS ONE. 2009;4:e6661. PubMed
4. Evans JD, Seeger C. Differential effects of mutations in NS4B on West Nile virus replication and inhibition of interferon signaling. J Virol. 2007;81:11809-16. PubMed
5. Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005;79:1343-1350. PubMed
6. Hayashi J, Stoyanova R, Seeger C. The transcriptome of HCV replicon expressing cell lines in the presence of alpha interferon. Virology. 2005;335:264-75. PubMed
7. Guo JT, Zhu Q, Seeger C. Cytopathic and noncytopathic interferon responses in cells expressing hepatitis C virus subgenomic replicons. J Virol. 2003;77:10769-79. PubMed
8. Zhu Q, Guo JT, Seeger C. Replication of hepatitis C virus subgenomes in nonhepatic epithelial and mouse hepatoma cells. J Virol. 2003;77:9204-10. PubMed