Emmanuel Thomas, M.D., Ph.D.
Assistant Professor of Cell Biology
Description of Research
Hepatitis C virus (HCV) is an RNA virus classified within the Flaviviridae family. There are approximately 4 million individuals in the United States with chronic infection making HCV the most common chronic blood-borne infection in the United States and there are approximately 170 million individuals infected globally. Chronic inflammation resulting from HCV infection causes a significant percentage of all cases of hepatocellular carcinoma (HCC) and it is the most frequent cause of liver transplantation. HCC is one of the few cancers whose incidence is on the rise and this cancer is predicted to continue to increase in incidence through 2020 due to the aging HCV infected population in the United States. Although, HCV is a particularly difficult pathogen to study in-vitro, research focused on this particular virus is yielding tremendous insight into host responses to virus infections in general. My research focus is aimed at limiting the morbidity and mortality associated with HCV infection and the subsequent development of HCC through several broad efforts. The first involves defining the intrinsic innate immune response hepatocytes mount immediately following infection with HCV. The second area of research is focused on determining the antiviral mechanisms of action of the agents used to treat HCV infection (i.e. interferon and ribavirin). Data gleaned from these studies will be utilized to develop novel antivirals and innovative treatment regimens for HCV infected individuals. In addition, a better understanding of hepatocyte-specific antiviral pathways may lead to the identification of adjuvants that specifically stimulate hepatocytes to strengthen the efficacy of vaccines targeting HCV. Lastly, we have initiated several clinical studies aimed at preventing HCC.
Specific areas of interest of the laboratory program include the function of the type III interferons (IFNs) also know as interferon lambda (λ). There are three different type III IFNs and they are designated as IFNλ 1,2 and 3 or IL29, IL28A and IL28B, respectively. These interferons are specifically produced by hepatocytes in response to HCV infection. The IFNs are secreted from the cell, and following interaction with specific cellular receptors, mediate their action by inducing the expression of numerous genes, many of which exert potent antiviral and antitumor activity. Although, type I (α,β) and III IFNs induce similar genes, they do so with different kinetics and they also demonstrate tissue specific expression with the type III IFNs mainly produced by hepatocytes and other epithelial cells.
Another area of research is focused on increasing our understanding of the antiviral mechanisms of action of the agents used to treat HCV infection. Currently, the “standard of care” treatment regimen for HCV is combined therapy with interferon, ribavirin and a viral protease inhibitor. Interferon and ribavirin’s mechanisms of action are poorly characterized. Although there are several proposed mechanisms of action, each with some supporting experimental evidence, there is no consensus as to their predominant mechanism of action for these antiviral agents. It is hoped that a better understanding of the mechanism of action of these agents will lead to improvements in the current treatment regimen. My work on these antiviral agents focuses on studying their mechanisms of action using data obtained from cell culture models and corresponding clinical trials. Ultimately, data gleaned from these studies can be used to identify novel antiviral agents with activity against HCV as well as many oncogenic viruses by stimulating the innate antiviral response specifically in infected cells.
- Discovered the hepatitis C virus (HCV) induces type III interferons in primary human hepatocytes and also that this antiviral response is blunted in transformed hepatic cell lines.
- Elucidated a novel mechanism of action of ribavirin in antiviral therapy for HCV.
- Discovered new innate immune recognition pathways important for recognizing RNA virus infection.
- Innate Immune Responses to Hepatitis C Virus and its Role in Development of Hepatocellular Carcinoma.
- Innate Immune Responses to Hepatitis B Virus and its Role in Development of Hepatocellular Carcinoma.
- Clinical Studies Aimed at the Prevention of Hepatocellular Carcinoma.
Selected Cancer-Related Publications
- Thomas E, Ghany MG, Liang TJ: The Application and Mechanism of Action of Ribavirin in Therapy of HCV. Antiviral Chemistry and Chemotherapy. 2012 Sep 25;23(1):1-12. Read more »
- Thomas E, Gonzalez VD, Modi AA, Chen W, Noureddin M, Rotman Y, Liang TJ: Robust Induction of Type III Interferons and other Cytokines Defines a Unique Pattern of Innate Immunity to HCV Infection. Gastroenterology 2012 Apr;142(4):978-88. Read more »
- Thomas E: Genome-Wide Association Studies: “SNPing” Away at Liver Disease. Gastroenterology & Hepatology. June 2011, Vol. 7, Issue 6, Pages: 407-409. Read more »
- Thomas E, Feld JJ, Li Q, Hu Z, Fried MW, Liang, TJ: Ribavirin Potentiates Interferon Action by Augmenting Interferon-Stimulated Gene Induction in HCV Cell Culture Models. Hepatology. 2011 Jan;53(1):32-41 Read more »
- Feld JJ, Modi AA, El-Diwani R, Rotman Y, Thomas E, Koh C, Cherepanov V, Heller T, Ghany MG, Park Y, Hoofnagle JH, Liang TJ: S-adenosyl methionine improves early viral kinetics and interferon stimulated gene induction by the combination of peginterferon and ribavirin in previous hepatitis C genotype 1 non-responders. Gastroenterology. 2011 Mar;140(3):830-9. Read more »
- Thomas E and Fried MW: Hepatitis C: Current Options for Nonresponders to Peginterferon and Ribavirin. Current Gastroenterology Reports. 2008 Feb;10(1):53-9. Read more »
Collaborating in the Multidisciplinary Research Program(s):