Our study focuses on chronic hepatitis infection – i.e. on hepatitis B, C and delta viruses (HBV, HCV, HDV). They often induce chronic liver disease and persistent inflammation that lead to progression of fibrosis, incidence of liver cirrhosis and cancer. Despite existence of effective vaccines towards HBV/HDV and treatment schemes for chronic hepatitis C, these infections are still far from global elimination, which has been announced as a goal for 2030. Moreover, 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. We have shown that HCV suppresses metabolism of biogenic polyamines, interfere with expression of arginase I and promote proline catabolism (Zakirova et al, Cells 2024). Inhibitors of polyamine metabolism exhibit anti-HCV activity. Currently we are exploring how HCV affects influx and efflux of nutrients and the role of secreted nutrients in the development of liver diseases.
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, Cell Death Disease 2025).
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).
However, the major drawback of available HBV and HDV infectious in vitro models is the low percentage of infected cells. So, imprint of these viruses on metabolism we are registering are mostly indirect and come from paracrine effects on surrounding (non-infected) cells. So, we are utilizing single-cell sequencing approach to “look into” the infected cells in such heterogenous models to characterize direct virus effects and to identify cells permissivity/restriction factors.
