The hepatitis C virus (HCV) causes a chronic infection of the liver that affects almost 2% of the world’s population. It is a member of the flavivirus family, replicates in hepatocytes and triggers a number of host responses that lead to progressive liver injury and cancer. HCV typically produces chronic infections and viral-host interactions slowly lead to liver injury over several decades. Our lab is focused on the mechanisms by which HCV injures hepatocytes and sensitizes the liver to a number of other processes such as drug and alcohol toxicity. We have previously determined mechanisms by which the HCV core protein upregulates the mitochondrial Ca2+ entry process, increases mitochondrial superoxide production and sensitizes the liver to a Ca2+/ROS dependent cell death pathway. We have more recently become interested in how HCV subverts cellular antioxidant defenses and cell cycle control and how these phenomena combine with alcohol to cause liver fibrosis and carcinogenesis. Our lab focuses on cell biological approaches but we have several clinical and translational studies involving patients with chronic hepatitis C, alcoholic hepatitis and hepatocellular carcinoma. Specific ongoing projects are:
FOXO3a in Chronic Hepatitis C and Hepatocellular Carcinoma
FOXO transcription factors are critical for antioxidant defense enzymes and control of cell proliferation. We have shown that HCV induces specific changes in FOXO3 post-translational modifications and these lead to liver injury in mouse models and cytotoxicity in cell culture. Current projects are using a novel isoelectric focusing based technology in conjunction with mass spec to identify viral induced FOXO3a modifications and examine their impact on cell function. Translational studies in conjunction with colleagues in the Departments of Surgery and Pathology have identified FOXO3a modifications present in HCV-associated hepatocellular carcinoma and are examining the potential of FOXO manipulation as a therapeutic approach for HCC. This work uses both clinical specimens, transgenic mice and cell culture adapted HCV as experimental model systems.
HCV and Alcoholic Hepatitis
Hepatitis C patients who drink alcohol have more severe liver injury than those with either condition alone. We have developed transgenic mouse models that express HCV proteins and, when fed alcohol recapitulate the accelerated liver injury seen in patients. Ongoing work is examining mitochondrial protein oxidation and redox signaling events in this process. In addition we have identified mitochondrially active antioxidant compounds that can prevent this process and are evaluating these as potential therapeutic agents.
The HCV p7 Viral Ion Channel and Regulation of Autophagy
Previous work in the lab has shown that the HCV p7 ion channel causes alkalinization of intracellular organelles and is required for virus particle production. Ongoing research is examining how these and other effects of HCV infection interfere with trafficking and vesicular fusion and modify autophagy pathways.
Resistance mutations define specific antiviral effects for inhibitors of the hepatitis C virus p7 ion channel.
Foster TL, Verow M, Wozniak AL, Bentham MJ, Thompson J, Atkins E, Weinman SA, Fishwick C, Foster R, Harris M, Griffin S. Hepatology. 2011 54:79-90.
Antioxidants as therapeutic agents for liver disease. Singal AK, Jampana SC and Weinman SA. Liver International 2011, 31:1478-3223
Wozniak, A.L., Griffin, S., Rowlands, D., Harris, M., Yi, M., Lemon, S.M., Weinman, S.A. Intracellular proton conductance of the hepatitis C virus p7 and its contribution to infectious virus, Plos Pathogens, 2010 Sep 2;6(9):e1001087.
Wang, T., Campbell, R.V., Yi, M., Lemon, S.M., Weinman, S.A., Role of hepatitis C core protein in viral-induced mitochondrial dysfunction, J Viral Hepatitis,2010,17(11):784-793.
Szabo G, Wands JR, Eken A, Osna NA, Weinman SA, Machida K, Joe Wang H., Alcohol and Hepatitis C Virus-Interactions in Immune Dysfunctions and Liver Damage. Alcohol Clin Exp Res. 2010, 34:1675-86.
Campbell RV, Yang Y, Wang T, Rachamallu A, Li Y, Watowich SJ, Weinman SA. (2009) Effects of Hepatitis C core protein on mitochondrial electron transport and production of reactive oxygen species. Methods Enzymology, 456: 363-80.
Osna, N.A., White, R.L., Krutik, V.M, Wang, T., Weinman, S.A., Donohue, T.M.. Proteasome activation by hepatitis C core protein is reversed by ethanol-induced oxidative stress. Gastroenterology 2008 Jun;134(7):2144-52.
Li, Y., Boehning, D.F., Qian, T., Popov, V.L., Weinman, S.A., Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity. FASEB Journal, 2007, 21:2474-85.
Chen, Z., Benureau, Y., Rijnbrand, R., Yi, J., Wang, T., Warter, L., Lanford, R.E., Weinman, S.A., Lemon, S.M., Martin, A., Li, K. GB virus B disrupts RIG-I signaling by NS3/4A-meditated cleavage of the adaptor protein MAVS. J. Virol, 2007, Jan;81(2):964-76. Epub 2006 Nov 8.
Loo, YM., Owen, DM., Li, K., Erickson, AK., Johnson, CL., Fish, CL., Carney, DS., Wang, T., Ishida, H., Yoneyama, M., Fujita, T., Satio, T., Lee, WM., Hagedorn, CH., Lau, DT., Weinman, SA., Lemon, SM., Gale, M, Jr.Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci USA, 2006 Apr 11;103(15):6001-6. Epub 2006 Apr 3.
Korenaga, M., Wang, T., Li, Y., Showalter, L., Chan, T., Sun, J., Weinman, S.A. Hepatitis C Virus Core Protein inhibits mitochondrial electron transport and increases ROS production. J.Biol Chem, 2005 Nov 11; 280(45):37481-8. Epub 2005 Sep 8.
Otani, K., Korenaga, M., Beard, M.R., Li, K., Qian, T., Showalter, L.A., Singh, A.W., Wang, T., Weinman, S.A. Hepatitis C virus core protein, cytochrome P450 2E1, and alcohol produce combined mitochondrial injury and cytotoxicity in hepatoma cells. Gastroenterology,2005 128:96-107.
Ann Wozniak, Ph.D., Postdoctoral Research Fellow
Jie Zhao, Research Associate
Kellyann Jones, Graduate Student
Jinyu Ren, Ph.D., Research Assistant Professor
Irina Tikhanovich, Ph.D., Postdoctoral Research Fellow
Sudha Kuravi, Research Associate
Josiah Cox, MD-PhD Student