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In recognition of World Hepatitis Day, we have made Ralf Bartenschlager July’s featured Faculty Member of the Month. Ralf is a molecular and cell biologist heading a virology research team at Heidelberg University and the German Cancer Research Center. His research is focused on analysing and comparing dengue and hepatitis virus to understand how these viruses interfere with the immune response and exploit the host machineries to establish their membranous replication organelles.

Can you tell us a little bit about your work?

I investigate the interaction of viruses with their host cells. By studying the hepatitis B virus (HBV) and doing comparative analyses between hepatitis C virus (HCV) and related Flaviviruses, such as Dengue virus (DENV) and Zika virus (ZIKV), we are interested in how these pathogens exploit or rewire the host cell to achieve robust replication. We want to understand how these viruses induce and counteract the innate immune response to develop or improve prophylactic and therapeutic concepts to prevent or treat infections with these viruses.

We are combining classical molecular and cell biological methods with cutting-edge imaging approaches that provide the spatial and temporal resolution required to analyze these processes. With respect to viral replication, we focus on how HCV and DENV/ZIKV create their membranous cytoplasmic replication organelle and which host cell lipids and proteins are involved in these processes.

We work to identify cellular pathways that are commonly used by these viruses and might be suitable targets for broad-spectrum antiviral drugs, and eventually devise novel concepts for a (functional) cure of HBV infection.

What triggered your interest in research?

While I was at school I was most interested in biology, a passion that was stimulated by a very dedicated teacher. I finished school, and after an interim period as police officer, I studied biology at Heidelberg University. During that time, I developed a growing interest in viruses. I found them fascinating, due to their extreme genetic economy and medical relevance.

I was lucky that a world leader in HBV research was working on our campus, Prof. Heinz Schaller, who became my mentor. I managed to work in his lab and was impressed by his scientific work and thinking. He and his team taught me a lot and Heinz prepared me for my independent scientific career. From all people I have met in my scientific life, Heinz has inspired and influenced me most.

What should researchers focus on to meet global viral hepatitis targets?

In my opinion, the most urgent problems in viral hepatitis are the lack of a curative therapy for chronic hepatitis B, the lack of a therapy for hepatitis D virus (HDV) infections and the lack of a prophylactic vaccine to prevent HCV infections. Considering the first point, there are around 230 million people persistently infected with HBV, despite the availability of a prophylactic vaccine. These people have a high risk to develop chronic liver disease including liver cirrhosis and hepatocellular carcinoma.

Our antiviral drugs can suppress HBV, but we don’t have a cure. All our current drugs have the same target, the viral reverse transcriptase/polymerase, but they don’t address the HBV persistence reservoir, which is the cccDNA. We need to study the cellular and immunological aspects of HBV persistence in much greater detail to come up with better approaches for a functional cure of control chronic hepatitis B.

We need to overcome the predominant thinking that the “HCV problem is solved” and devise new concepts.

In the case of HDV, we have little understanding of the basic mechanism and how this virus needs HBV as a helper, replicates and spreads in the liver. Drug development is very difficult and requires either targeting a host cell factor promoting HDV replication or blocking the early (infection) stage.

HCV infections can be cured in the vast majority of infected individuals. However, the therapy is costly and not available in most countries with high HCV prevalence. Reinfection is possible even after successful cure. To achieve global HCV eradication, we need a prophylactic vaccine. In order to do this, we need to overcome the current predominant thinking that the “HCV problem is solved” and devise new concepts on how to produce an antigen that provides a broadly protective immune response.

What was your last recommendation and why did you pick it?

My colleague Marco Binder and I picked an extremely interesting report by the group of Raoul Andino at UCSF (Tassetto et al., Cell 2017). They reported a previously unknown mechanism on how fruitflies (Drosophila) amplify and sustain a nuclease-based antiviral response. We are aware that humans have quite a complicated immune system that is able to fight pathogens with high efficiency, but what about simple organisms such as flies? They rely on an ancient mechanism called RNA interference. The study by Tassetto and colleagues shows how this antiviral defense is “archived” in distinct immune cells (the haemocytes), and how it is spread systemically. They describe a pathway of an immunological memory that lasts for several weeks and for a considerable part of the fruitflies’ lifespan.

This is a fascinating and surprising result, as we have described in our recommendation: “This story has it all: retro-transposons, immunological memory in lower organisms, and intercellular communication by exosomes”.  It also reveals some remarkable parallels to the famous CRISPR/Cas system and how an RNAi response can spread systemically in an animal.

Research in infectious diseases has departed from a pathogen-centric view to a more global analysis of the complexities of pathogen – host interaction.

It is a contemporary holistic view to studying pathogens, addressing the complex interface between host cells and pathogens. In the past, we and many other scientists focused more on the pathogen itself, e.g., by doing extensive mutagenesis and looking for the impact of given mutations on pathogen replication and spread.

Research in infectious diseases has departed from a pathogen-centric view to a more global analysis of the complexities of pathogen – host interaction, helped with the advent of modern technologies that allow us to study, e.g., the impact of a pathogen on the complete host genome, transcriptome or proteome rather than analysing an individual gene or gene product. Although Tassetto and colleagues did not use such methodology, it is a nice example of how research in infectious diseases has evolved.

What would you say is the best piece of career advice that you received and that you would like to pass on to early career researchers?

A scientist should have a strong interest in the topic he/she is working on, have (and remain) curious, and be eager to make new discoveries. Presentation skills are essential, as you need to present your results both to the experts and the general public, not only to promote your work, but also to secure adequate funding. Finally, you should be self-confident.

There is no doubt that working as a scientist is more than just a profession and can often mean working beyond the regular 9-5. Despite the long hours, the drive comes from the strong interest in the topic, along with the freedom to select your subject area largely independent from external influences. If these traits resonate with you, then a research career could be the perfect choice for you.