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Hepatitis

Hepatitis: From dysregulated
lipid metabolism to lasting liver failure

According to the World Health Organization, 1.3 million people die each year of hepatitis. In the United States, liver damage due to chronic infection with hepatitis B or C viruses is the leading cause of liver transplants. Our lab studies the three main hepatitis viruses (HAV, HBV and HCV), with a special focus on fat metabolism in liver cells and the use of 3D liver models to study spreading infection.

Lipid droplets: a lifeline for HCV, and many others pathogens

HCV interacts with lipid metabolism in liver cells at many stages of its life cycle. Our work demonstrated that the last step is directly intercepted by HCV via an interaction of the viral core protein and diacylglycerol acetyltransferase-1 (DGAT1). This interaction translocates the viral core proteins onto the surface of lipid droplets — which is crucial to producing new virions. Core also decreases lipid droplet turnover, leading to fat accumulation (steatosis) in both mice and cell culture cells, connecting these molecular mechanisms directly with the fatty liver syndromes observed in people living with HCV.

Many viruses usurp the fat metabolism to complete their life cycle. We characterized how hepatitis C virus (HCV) increases triglyzeride content in infected livers and exploits lipid droplets for its own virion assembly. We also showed that SARS-COV-2 and two coronaviruses responsible for common colds rely extensively on cholesterol uptake and de novo synthesis for their propagation. Our research into lipid metabolism may lead to new approaches to fight viruses, including SARS-CoV-2.

Hepatitis and liver damage: Clues from liver organoids

To understand how hepatitis viruses may cause lasting liver damage, we grow organoids (3D mini organs) derived from primary liver cells of infected or uninfected individuals. We developed new ways to coculture liver organoids with immune cells to study how the antiviral immune response may cause damage and how it can be strengthened to allow viral eradication.

Beyond lipids: finding host factors for hepatitis viruses via large-scale genomics and proteomics

We carry out large screens to identify hepatitis viruses’ host factors, both at the proteomics and genomics level. In a protein: protein interactome study with the Krogan lab, we found that hepatitis C virus interferes with the host nonsense-mediated RNA decay pathway to avoid its antiviral activity. A genome-wide CRISPR screen by the Puschnik lab identified two host factors that the hepatitis A virus exploits to translate its own RNAs. These studies may help to develop new antiviral drugs and may improve clinical care in the future.