Name: Maura Dandri
Institution: University Medical Center Hamburg-Eppendorf, Hamburg
Location: Hamburg, Germany
Could you tell me a little bit about your research and what it entails?
The overall aim of my research is to understand the mechanisms by which human hepatitis viruses engage with the host to accomplish their replication requirements and how that may be determinant of both infection persistence and pathogenesis. In particular, my lab group is interested in investigating the interplay that the hepatitis B virus (HBV) establishes with the human hepatocyte in the course of infection. Because of the narrow host range of HBV infection, there are only a few experimental systems available which permit to exploit the impact of HBV on hepatocyte functions. Thus, we focused our research on the establishment of infection models enabling long-term maintenance of primary human hepatocytes susceptible to infection with human hepatitis viruses. Having first demonstrated the feasibility of recapitulating the entire life cycle of HBV in mice harbouring a liver partially reconstituted with primary human hepatocytes, we are currently interested in studying mechanisms affecting the stability and activity of the HBV persistence form in the cell nucleus. We are also involved in preclinical studies testing new antiviral compounds and therapeutic strategies. Moreover, we study how HBV infection, as well as the hepatitis D virus (HDV), interferes with the intrinsic innate immune responses and metabolic pathways of infected cells, since such alterations may play a major role in determining infection persistence and long-term pathogenesis.
How did you come to be interested in viral hepatitis?
I was still taking molecular biology classes as a student at the University of Trieste, in Italy, when I first learned about different mechanisms that viruses adopt to hijack cellular processes and how viruses can be directly involved in carcinogenesis. In this regard, chronic infection with HBV is considered a major risk factor for liver cancer development. In that class and during my PhD training at the Albert Einstein College of Medicine in New York I became even more aware of the global health burden caused by viral hepatitis infections and of the need to develop more effective antiviral treatments. Moreover, I found it fascinating how these infectious agents can so elegantly manipulate the cellular machinery for their purposes without raising strong host responses. I also think that studies of virus-host interactions represent an enthralling field of research offering unique possibilities to learn about fundamental cellular processes which have been exploited by viruses for a long time but that are still new to us.
What do you see as the biggest accomplishment in your field in the past few years?
In the case of HCV, replicon-based cell culture systems and later on infection models have been crucial for high throughput testing and development of potent HCV inhibitors permitting viral clearance. Achieved five years ago, the identification of the cellular receptor responsible for cell entry of HBV and HDV represents the biggest accomplishment of the past few years, since it has opened new possibilities to establish in vitro infection systems enabling faster screening of new drugs targeting these viruses. The availability of both humanized mice and improved in vitro systems is expected to accelerate the development of improved therapies.
What do you see as the main challenges for research in your field in the coming years?
The successful development of antiviral therapies for HCV has raised hope about the possibility to obtain a cure also for other chronic viral liver infections. However, despite the availability of an effective vaccine to prevent HBV infection and antivirals efficiently suppressing viral replication, resolution of HBV infection is rarely achieved. This is mostly due to the persistence of the HBV genome, the so-called cccDNA, in the nucleus of infected hepatocytes, as well as to the inability of the immune system to efficiently counteract chronic HBV infection. In particular, elimination of the cccDNA from the infected cells remains very challenging. Exploring interventions able to destabilize or silence the cccDNA, as well as improving understanding of the immunological mechanisms permitting HBV persistence, will be essential for the development of therapeutic approaches able to cure HBV infection. Furthermore, there is a strong medical need to develop drugs that block HDV replication and prevent HDV-induced liver disease progression. Despite all technical difficulties, I believe that the availability of improved in vitro and in vivo systems will be determinant for the development of therapeutic strategies permitting to cure also HBV and HDV chronic infection.
Immunofluorescence micrograph showing human hepatocytes (CK-18, light blue) infected with HBV (HBcAg, green) and with HDV (HD-Ag, red) within the mouse liver. All nuclei visible in dark blue (DAPI). Courtesy of M. Dandri.
What personal career achievement are you most proud of? Why?
I am very proud that the German Research Foundation (DFG) has awarded me with a Heisenberg professorship to study hepatitis viruses and that the University Medical Center Hamburg-Eppendorf strongly supported this professorship and my career. Perhaps a less official but very important achievement in my career was when 18 years ago the first HBV-infected human liver chimeric mouse was generated in our lab. This proof of principle cornerstone gave the group and perhaps also other researchers the right impulse to progress in the development of such precious small animal models that are now used worldwide in viral hepatitis research.