Immunology of Viral Hepatitis and Infections in Liver Cirrhosis
Our research
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.
Our research
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.
Group leaders
Markus Cornberg is W3-Professor Infectious Diseases with a focus on Hepatology and Deputy Director of the Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology at Hannover Medical School, Germany. Since 2019, he is Clinical Director of the Helmholtz Centre for Infection Research and Director of the Centre for Individualized Infection Medicine (CIIM). Prof. Cornberg is Medical Executive Director of the German Liver Foundation. Since 2007, Prof. Cornberg has coordinated the German guideline on the management of hepatitis B virus infection. From 2017 to 2020, he served on the Scientific Committee and Governing Board of the European Association for the Study of the Liver (EASL). He has been Associate Editor of the Journal of Hepatology since 2019. His basic science research focus is the investigation of cellular immune responses for disease progression and treatment response in patients with viral hepatitis. Prof. Cornberg has published >300 original scientific papers as well as review articles.
Anke Kraft is a senior scientist in the Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology at Hannover Medical School and in the Centre for Individualized Infection Medicine (CIIM). She studied biology in Göttingen and Braunschweig and received her PhD from the University of Würzburg. After research stays at the University of Essen, Worcester (MA, USA) and Hannover, she has been leading the research group "Immunology of viral hepatitis and infections in liver cirrhosis" together with Markus Cornberg since 2018. She is a member of the German Society for Virology (GfV) and for Immunology (DGFI) and works as Review Editor at Frontiers Immunology. Anke Kraft has been working on immune responses in chronic viral infections for more than 20 years. She is interested in developing novel strategies to restore T cell responses in chronic viral infections and patients with advanced liver cirrhosis. Her current work includes studying hepatitis virus-infected patients and working on knowledge graphs to better understand the patient immune system, as well as chronic mouse models.
Selected Publications
Aliabadi E, Urbanek-Quaing M, Maasoumy B, Bremer B, Grasshoff M, Li Y, Niehaus CE, Wedemeyer H, Kraft ARM, Cornberg M. Impact of HBsAg and HBcrAg levels on phenotype and function of HBV-specific T cells in patients with chronic hepatitis B virus infection. Gut. 2022 Nov;71(11):2300-2312. doi: 10.1136/gutjnl-2021-324646.
Cornberg M, Mischke J, Kraft AR, Wedemeyer H. Immunological scars after cure of hepatitis C virus infection: Long-HepC? Curr Opin Immunol. 2023 Jun;82:102324. doi: 10.1016/j.coi.2023.102324.
Oltmanns C, Liu Z, Mischke J, Tauwaldt J, Mekonnen YA, Urbanek-Quaing M, Debarry J, Maasoumy B, Wedemeyer H, Kraft ARM, Xu CJ, Cornberg M. Reverse inflammaging: Long-term effects of HCV cure on biological age. J Hepatol. 2023 Jan;78(1):90-98. doi: 10.1016/j.jhep.2022.08.042.
Niehaus CE, Strunz B, Cornillet M, Falk CS, Schnieders A, Maasoumy B, Hardtke S, Manns MP, Kraft ARM, Björkström NK, Cornberg M. MAIT Cells Are Enriched and Highly Functional in Ascites of Patients With Decompensated Liver Cirrhosis. Hepatology. 2020 Oct;72(4):1378-1393. doi: 10.1002/hep.31153.
Klein S, Mischke J, Beruldsen F, Prinz I, Antunes DA, Cornberg M, Kraft ARM. Individual Epitope-Specific CD8+ T Cell Immune Responses Are Shaped Differently during Chronic Viral Infection. Pathogens. 2023 May 14;12(5):716. doi: 10.3390/pathogens12050716.
