The Role of Oxidative Stress in Viral Hepatitis

Viral hepatitis represents one of the greatest challenges to human health with more than 500 million people being infected with either hepatitis B virus (HBV) or hepatitis C virus (HCV). The pathogenesis is notoriously complex and involves an intricate interplay of viral and host factors that determine the clinical outcome. Virus-induced oxidative stress is considered to play a crucial role in hepatitis. The host features several counteracting layers of anti-oxidative protection, yet, little is known about their individual contributions to viral hepatitis. In this project we want to dissect the functional role of individual members of the anti-oxidative system in viral hepatitis. For this we employ a well-defined hepatitis mouse model using lymphocytic choriomeninigitis virus (LCMV). In the past seminal findings in the areas of immunology and host-pathogen interactions have been made with LCMV, two of which led to Nobel Prizes. This model provides great experimental versatility as well as patho- physiological relevance to human disease. Our results should contribute to a deepened understanding of how virus-induced oxidative stress contributes to liver damage. Advances therein may have significant translational impact for the treatment of the many patients who suffer from HBV or HCV.

Viral hepatitis is a global health problem, affecting more than 500 million people worldwide. However, the molecular mechanisms leading to liver damage are still not well understood since they involve a complex interplay of factors both on the viral side and on the host side. The host employs an elaborate immune response to fight off viruses. In the early phase of the infection, potent antiviral molecules called type-I interferons (IFN-I) are rapidly produced to restrict the viral spread. Yet, the pleiotropic effects of IFN-I are still not fully understood and contain surprises. In the present study published in the prestigious journal Immunity, the research group of Andreas Bergthaler at CeMM together with other international groups identified a novel effect of IFN-I, which provides a new paradigm of how viral infections damage the liver. Unexpectedly, IFN-I was found to induce oxidative stress in liver cells. Oxidative stress is a phenomenon that occurs when the oxidative metabolism leads to the accumulation of highly reactive oxygen radicals that cannot be efficiently removed by antioxidant mechanisms inside the cell. This study describes how oxidative stress is initiated by IFN-I, which then causes damage to the liver cells. This detrimental effect of IFN-I is counteracted by the host antioxidant enzyme superoxide dismutase 1, which, itself is however repressed by IFN-I. Together, our findings delineate IFN-I induced oxidative stress as a key mediator of virus- induced liver damage. This study unravels a novel link between antiviral IFN-I signaling and oxidative metabolism, thereby shedding light on the complex molecular processes that lead to tissue damage in viral hepatitis. The involved mechanisms are likely to occur in other diseases with elevated IFN-I levels and, thus, may bear broader relevance. Future research is aimed to investigate the beneficial and detrimental consequences of IFN-I and may lead to the discovery of new therapeutic strategies to protect from infectious and inflammatory diseases.