World-wide 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 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.
World-wide 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.
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 cooked 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 can progress rapidly within a few years to liver cirrhosis. 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.
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.
The impact of HCV cure on the immune system
Hengst J, Strunz B, Deterding K, Ljunggren HG, Leeansyah E, Manns MP, Cornberg M, Sandberg JK, Wedemeyer H, Björkström NK. Nonreversible MAIT cell-dysfunction in chronic hepatitis C virus infection despite successful interferon-free therapy. Eur J Immunol. 2016; 46:2204-2210.
Hengst J, Falk CS, Schlaphoff V, Deterding K, Manns MP, Cornberg M, Wedemeyer H. Direct-Acting Antiviral-Induced Hepatitis C Virus Clearance Does Not Completely Restore the Altered Cytokine and Chemokine Milieu in Patients With Chronic Hepatitis C. J Infect Dis. 2016; 214:1965–1974.
Strunz B, Hengst J, Deterding K, Manns MP, Cornberg M, Ljunggren HG, Wedemeyer H, Björkström NK. Chronic hepatitis C virus infection irreversibly impacts human natural killer cell repertoire diversity. Nat Commun. 2018; 9:2275
Hengst J, Klein AL, Lunemann S, Deterding K, Hardtke S, Falk CS, Manns MP, Cornberg M, Schlaphoff V, Wedemeyer H. Role of soluble inflammatory mediators and different immune cell populations in early control of symptomatic acute hepatitis C virus infection. J Viral Hepat. 2019; 26:466–475.
Aregay A, Owusu Sekyere S, Deterding K, Port K, Dietz J, Berkowski C, Sarrazin C, Manns MP, Cornberg M*, Wedemeyer H*. Cure of Hepatitis C Virus has limited impact on the functional and mitochondrial impairment of HCV-specific CD8+ T cell response. J Hepatol 2019; in press. * contributed equally
The impact of immune responses on HBV cure
Höner Zu Siederdissen C, Rinker F, Maasoumy B, Wiegand SB, Filmann N, Falk CS, Deterding K, Port K, Mix C, Manns MP, Herrmann E, Wedemeyer H, Kraft AR, Cornberg M. Viral and Host Responses After Stopping Long-term Nucleos(t)ide Analogue Therapy in HBeAg-Negative Chronic Hepatitis B. J Infect Dis. 2016; 214:1492–1497.
Berg T, Simon KG, Mauss S, Schott E, Heyne R, Klass DM, Eisenbach C, Welzel TM, Zachoval R, Felten G, Schulze-Zur-Wiesch J, Cornberg M, Op den Brouw ML, Jump B, Reiser H, Gallo L, Warger T, Petersen J, FINITE CHB study investigators [First investigation in stopping TDF treatment after long-term virological suppression in HBeAg-negative chronic hepatitis B. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study. J Hepatol. 2017; 67:918–924.
Rinker F, Zimmer CL, Höner Zu Siederdissen C, Manns MP, Kraft ARM, Wedemeyer H, Björkström NK*, Cornberg M*. Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B. J Hepatol. 2018; 69:584–593. * contributed equally
Zimmer CL, Rinker F, Höner Zu Siederdissen C, Manns MP, Wedemeyer H, Cornberg M*, Björkström NK*. Increased NK Cell Function After Cessation of Long-Term Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Is Associated With Liver Damage and HBsAg Loss. J Infect Dis. 2018; 217:1656–1666. * contributed equally
Höner Zu Siederdissen C, Hui AJ, Sukeepaisarnjaroen W, Tangkijvanich P, Su WW, Nieto GEG, Gineste P, Nitcheu J, Crabé S, Stepien S, Manns MP, Trépo C, Wedemeyer H, Cornberg M. Contrasting Timing of Virological Relapse After Discontinuation of Tenofovir or Entecavir in Hepatitis B e Antigen-Negative Patients. J Infect Dis. 2018; 218:1480–1484.
The impact of immune responses in chronic hepatitis E
Al-Ayoubi J, Behrendt P, Bremer B, Suneetha PV, Gisa A, Rinker F, Manns MP, Cornberg M, Wedemeyer H, Kraft ARM. Hepatitis E virus ORF 1 induces proliferative and functional T-cell responses in patients with ongoing and resolved hepatitis E. Liver Int. 2018; 38:266–277.
Gisa A, Suneetha PV, Behrendt P, Pischke S, Bremer B, Falk CS, Manns MP, Cornberg M, Wedemeyer H, Kraft AR. Cross-genotype-specific T-cell responses in acute hepatitis E virus (HEV) infection. J Viral Hepat. 2016 Apr;23(4):305-15. doi: 10.1111/jvh.12495. Epub 2016 Feb 8.
Soon CF, Behrendt P, Todt D, Manns MP, Wedemeyer H, Sällberg Chen M, Cornberg M. Defining Virus-specific CD8+ TCR Repertoires for Therapeutic Regeneration of T Cells against Chronic Hepatitis E. J Hepatol. 2019. doi: 10.1016/j.jhep.2019.06.005.
Understanding of the Cirrhosis Associated Immune Deficiency Syndrome
Tergast TL, Wranke A, Laser H, Gerbel S, Manns MP, Cornberg M*, Maasoumy B*. Dose-dependent impact of proton pump inhibitors on the clinical course of spontaneous bacterial peritonitis. Liver Int. 2018; 38:1602–1613. * contributed equally
Tergast TL, Laser H, Gerbel S, Manns MP, Cornberg M*, Maasoumy B*. Association Between Type 2 Diabetes Mellitus, HbA1c and the Risk for Spontaneous Bacterial Peritonitis in Patients with Decompensated Liver Cirrhosis and Ascites. Clin Transl Gastroenterol. 2018; 9:189. * contributed equally
Kimmann M, Tergast TL, Schultalbers M, Laser H, Gerbel S, Manns MP, Cornberg M, Maasoumy B. Sustained impact of nosocomial-acquired spontaneous bacterial peritonitis in different stages of decompensated liver cirrhosis. PLoS One. 2019 Aug 2;14(8):e0220666. doi: 10.1371/journal.pone.0220666.