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Immunology of Viral Hepatitis and Infections in Liver Cirrhosis

Hepatitis viruses A-E pose a major health challenge worldwide. Acute infections with hepatitis B (HBV), C (HCV), D (HDV) or E (HEV) can progress to chronic hepatitis and lead to liver cirrhosis and hepatocellular carcinoma. Chronic viral hepatitis affects more than 350 million people worldwide. While direct-acting antiviral drugs provide a cure for chronic hepatitis C, the long-term effects on the immune system after the infection is cured are not fully understood. While direct-acting antiviral nucleos(t)ide analogues can treat chronic hepatitis B, complete cure is rare. Innovative approaches, particularly modulation of the immune response to HBV, hold promise for a cure. Chronic hepatitis D is always a co-infection with HBV and thus concepts to cure HBV will also target HDV. In chronic hepatitis E, which is unique in immunocompromised patients such as organ transplant patients, enhancing the immune response against HEV may be a novel strategy. In people with cirrhosis of the liver, regardless of the cause, the immune system is compromised and susceptibility to infection is increased. In particular, bacterial infections of the peritoneal cavity due to ascites contribute significantly to disease progression. Our research group focuses on understanding immune responses to hepatitis viruses and developing biomarkers to better stratify patients for new therapeutic strategies to modulate the host immune system in the effort to combat chronic viral hepatitis. In addition, we are exploring the mechanisms underlying immunodeficiency in liver cirrhosis and investigating immunomodulation strategies to improve survival in these vulnerable patients.

Head

Prof Dr Markus Cornberg and Prof Dr Anke Kraft

Department head

Focus

The Impact of immune responses on chronic hepatitis B virus

Worldwide more than 250 million people are chronically infected with hepatitis B virus (HBV) with 650.000 HBV related death annually. Current treatment options for chronic hepatitis B in industrialized countries are the cytokine interferon alfa or direct antivirals, so called nucleos(t)id-analoga (NA). NA can suppress viral replication very efficiently. However, only a small percentage of patients will achieve a status of functional cure, which is measured by the loss of the HBV envelope antigen (HBsAg). The reason is that NA therapy only inhibits the generation of new virions, but does not directly affect the mini-chromosome of HBV that is located in the nucleus of the liver cell. This so called covalently closed circular HBV DNA (cccDNA), the template of HBV, might be eliminated by new strategies involving immune responses. One focus of our research group is to understand mechanisms of the immune system to clear HBV and to identify new targets for therapeutic interventions for HBV cure.

The impact of HCV cure on the immune system

Worldwide 50-70 million people are chronically infected with HCV. Chronic hepatitis C leads to liver cirrhosis and increases the risk to develop liver cancer. In addition, infection with HCV can cause extrahepatic manifestations such as chronic fatigue or certain rheumatic diseases. Chronic HCV infection leads also to an altered and dysregulated immune response, which might also impact extrahepatic symptoms. Treatment with direct acting antivirals (DAA) have been established in 2014 and HCV cure can be achieved in more than 95% of treated patients. HCV cure prevents the development of cirrhosis and reduces the risk to develop liver cancer. However, the risk for cancer is not zero and extrahepatic manifestations are not always reversed. The short and long-term effect of HCV cure on the imbalanced immune system is a main focus of our research. A better understanding of immune responses in HCV might also foster the progress to find a vaccine against HCV which is important to achieve WHO elimination goals of HCV infection.

The impact of immune responses in chronic hepatitis E

Infection with the hepatitis E virus (HEV) is considered as the most common cause of acute viral hepatitis in developing as well as in developed countries. Infections in industrialized countries are mainly zoonotic infections with genotype 3, which is transmitted by consumption of raw or undercooked meat or viscera of infected animals, or through contaminated blood products.

Patients with acute hepatitis E usually recover spontaneously and clear the virus but immunosuppressed patients, such as solid organ transplant recipients, may develop chronic hepatitis E in about 50% of cases. Patients with chronic hepatitis E may develop cirrhosis within a few years. There is no approved drug for chronic hepatitis E. Interferon-α or ribavirin are off-label treatment options and if used associated with side effects. One focus of the research group is to understand how the immune system can be modified to clear chronic HEV infection. This could lead to new concepts to treat immunocompromised patients with chronic hepatitis E.

Understanding of the Cirrhosis Associated Immune Deficiency Syndrome

Liver cirrhosis is the end-stage of many chronic liver diseases such as chronic hepatitis virus infections. Complications of cirrhosis are ascites or hepatic encephalopathy, as well as esophageal varices bleeding, which defines decompensated cirrhosis. Patients with decompensated cirrhosis have a one-year cumulative mortality of roughly 50%. The main cause for this high mortality is infection, such as spontaneous bacterial peritonitis (SBP). One reason for the vulnerability for infections is thought to be the impaired immune defense of patients with advanced liver cirrhosis, known as liver cirrhosis associated immune deficiency syndrome. One focus of our research group is to investigate soluble and cellular immune responses in the blood and the ascites of patients with decompensated liver cirrhosis to understand mechanisms of the immune deficiency and ways to manipulate and improve this condition.

Mouse models: To decode the effect of immune modulatory therapies on heterologous viral infections

Chronic viral infections are still a global health burden. For many of these infections therapy options for viral clearance are limited. One strategy to overcome chronicity is to target the host immune responses. Therefore, deeper insides in the mechanism how chronicity develops and how immune modulatory interventions (e.g. α-PD-L1 antibody therapy) might influence and shape the antiviral immune response is needed.

One focus of the research group is to use the well-established lymphocytic choriomeningitis virus (LCMV) mouse model to investigate new concepts of immune modulatory treatment options on viral clearance and modulation of the host immune responses.