Our study focuses on chronic hepatitis infection – i.e. on hepatitis B, C and delta viruses (HBV, HCV, HDV). These pathogens often induce chronic liver disease and persistent inflammation that lead to progression of fibrosis, incidence of liver cirrhosis and cancer. Despite existence of an effective vaccine towards HBV/HDV and treatment schemes for chronic hepatitis C, these viruses are still far from global elimination, which has been announced a goal for 2030. Moreover, even cure of HCV infection does not always prevent progression of fibrosis and incidence of end-stage liver disease. So, investigation of pathogenesis of these viral infections remains an important goal.
Previously we unveiled mechanisms by which HCV proteins enhance production of reactive oxygen species (Ivanov et al, Viruses 2015; Smirnova et al, Oxid Med Cell Longev 2016), demonstrated that they activate the Nrf2/ARE pathway (Ivanov et al, PLoS One 2011) and showed that the RNA-dependent RNA polymerase of the virus is regulated by S-glutathionylation (Kukhanova et al, Oxid Med Cell Longev 2019). We also contributed to the studies of Dr. Birke Bartosch who demonstrated that HCV induces glutathione peroxidase 4 (GPx4) for protection of its viral particles from inactivation via lipid peroxidases (Brault et al, Gut 2016) and that HCV remodulates ER-mitochondria contacts (Duponchel et al, JHep Rep 2023).
Our current activities in HCV research are focused on analysis of interplay between the virus with polyamine and proline metabolism as well as urea cycle (manuscript in preparation). We are also exploring if the inhibitors of metabolic enzymes can exhibit antiviral activity.
Hepatitis delta virus is a viroid like pathogen that infects individuals with hepatitis B and severely aggravates clinical course of the disease. We have analyzed impact of HDV infection of hepatocyte metabolism, mechanisms of the changes, and assessed their role in modulation of cell viability during various stress conditions (Khomich et al, submitted).
We have also shown that expression of the large virus antigen (L-HDAg) during replication of its genome or via its sole overexpression increases ROS production via several enzymes (NOX1, NOX4, CYP2E1, Ero1a), activates antioxidant Nrf2/ARE pathway and triggers unfolded protein response (Smirnova et al, Antioxidants, 2023).
