FUNDING OPPORTUNITIES
ProfessorCellular Pathogenesis of Hepatitis C
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 previously demonstrated that the viral core protein binds to mitochondria and upregulates Ca2+ entry into these organelles. This increases the mitochondrial production of reactive oxygen species, inhibits electron transport and alters cellular redox potential. Current work in the lab is exploring how these and other effects of the virus produce the observed liver disease. The goal of these studies is to target therapies to prevent the long-term consequences of viral infection. Specific areas of research are:
Mechanisms of HCV-Alcohol interactions
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, these mice 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.
Redox Signaling and Viral Induced Apoptosis
The recent development of cell culture infection models of HCV has shown that this virus is directly cytopathic and can both induce apoptosis and sensitize hepatocytes to apoptotic stimuli. Current work is using this model to study redox signaling events that trigger apoptosis, particularly involving MAPkinase pathways and protein S-nitrosylation.
Function of the p7 Viral Ion Channel
Another area of interest in the lab is how regulation of luminal pH in endocytic and secretory vesicles plays a role in the life cycle of HCV. Intravesicular pH control is critical to the lifecycle of Hepatitis C virus and an HCV protein, p7, has been suggested to function as a proton channel, specifically required for assembly of viral particles. Ongoing studies are determining how the p7 protein regulates the events necessary for viral entry, fusion, and infectious particle formation. The goal of these studies is to understand how the elements of the cellular pH regulatory system can be targets for antiviral drug development.
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
McCartney, E.M., Semendric, L., Helbig, K.J., Hinze, S., Jones, B., Weinman, S.A., Beard, M.R. Alcohol metabolism increases the replication of hepatitis C virus and attenuates the antiviral action of interferon. J Infect Dis. 198:1766-75, 2008
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 134:2144-2152, 2008
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, 21:2474-85, 2007
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, 81:964-976, 2007
Zhao, Z., Li, X., Hao, J., Winston, J., Weinman, S.A. The CIC-3 chloride transport protein traffics through the plasma membrane via interaction of an N-terminal dileucine cluster with clathrin. J. Biol. Chem, 282:29022-29031, 2007
Wang, T., Weinman, S.A., Causes and consequences of mitochondrial reactive oxygen species generation in Hepatitis C. J Gastroenterol Hepatol, 3:S34-7, 2006.
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, 103:6001-6006, 2006.
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, 280:45-37841, 2005.
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, 128:96-117, 2005.
When we try to pick out anything by itself, we find it is tied to everything else in the universe.
John Muir (1838-1914)
©
The University of Kansas Medical Center