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Study by international research teams opens up new possibilities for research on the pathogenesis of viruses - Hepatitis B viruses have existed for millions of years
Infections with the hepatitis B virus (HBV) are one of the major global health problems. More than 240 million people worldwide are chronically infected with this virus and over 887,000 people die each year from the long-term consequences of the infection, such as liver cirrhosis and liver cancer. New ways to study HBV pathogenesis are emerging from the discovery of an unusual HBV in shrews: this virus lacks an important immune modulator that is important for the chronification of infection. The teams of Prof. Dr. Dieter Glebe, head of the National Reference Centre for Hepatitis B and D Viruses at the Institute of Medical Virology of the Justus Liebig University Giessen (JLU), and Prof. Dr. Jan Felix Drexler, Institute of Virology of the Charité – Universitätsmedizin Berlin, together with other research groups from Germany and abroad, have now been able to prove this. In addition, the working group of Prof. Dr. Joachim Geyer, Institute of Pharmacology and Toxicology at the Department of Veterinary Medicine at JLU, is involved in the study. They examined about 700 shrew samples from Europe and Africa. Their study also shows that HBV has existed in mammals for millions of years. The results were published in the journal Proceedings of the National Academy of Sciences.
Chronification of HBV infection, which occurs particularly frequently in newborns, childhood and adolescent infections and often remains undetected for decades, is one of the main characteristics of this viral disease. In all mammalian HBV known to date, including human HBV, the viral protein HBeAg enables the chronification of the infection. This viral protein is produced during an infection. As an immunomodulator, it suppresses the body's specific immune defence against HBV, so that the infection cannot heal and becomes chronic – often with very high virus concentrations in the blood. In the absence of this viral protein, the body's immune system can successfully fight the starting infection.
The newly discovered HBV of shrews surprisingly do not have the genetic ability to produce the immunomodulator HBeAg. Despite the absence of HBeAg, the infected animals showed high levels of HBV virus in the blood. “This indicates a very successful but unusual infection characteristic and distribution of shrew HBV in its hosts,” said Prof. Glebe. “Since the virus is unable to infect human liver cells, an infection of humans with these viruses can very probably be ruled out. A danger for the general population in contact with HBV-infected shrews is therefore not to be assumed.” Shrews are protected species and are an important part of the ecosystem. In earlier work, this team of scientists was able to show that mammals other than humans carry their own HBV species and that some of these animal viruses can even infect human cells.
The second peculiarity of the newly discovered virus is that it does not use the liver bile acid transporter known so far from human and monkey HBV to infect its target cells, but instead takes a completely unknown path into the cell. “We still do not know all HBV receptor molecules,” said Prof. Drexler. “Third, our evolutionary biological investigations show that hepatitis B viruses have existed in mammals for millions of years, probably for 80 million years.”
The scientists now hope to further investigate the unusual infection behaviour of this shrew-HBV, which does not require the presence of the key immunomodulator HBeAg. Despite enormous international efforts, no effective therapy for the cure of chronic hepatitis B has yet been developed. One of the reasons for this is that there are no simple animal models that can be used to investigate the complex interactions of the viral infection with the host's immune system. “The HBVs of shrews that have now been discovered are bringing a suitable model for the investigation of HBV infection within reach,” said Prof. Glebe.
The work of the JLU teams of Prof. Glebe and Prof. Geyer was mainly carried out within the framework of the Collaborative Research Centre SFB 1021, which is funded by the German Research Foundation (DFG). The JLU, the Charité, the University of Bonn, the University Hospital Freiburg, the Bernhard-Nocht-Institute for Tropical Medicine in Hamburg, the Friedrich-Loeffler-Institute in Greifswald/Riems as well as universities and institutes in Sierra Leone, Nigeria, the Ivory Coast, Latvia and Russia participated in the study.
Prof. Dr. Dieter Glebe
National Reference Centre for Hepatitis B and D Viruses
Institute of Medical Virology
Justus Liebig University Giessen
Schubertstr. 81
35392 Giessen
Germany
Phone: +49 641 99-41246
Prof. Dr. Jan Felix Drexler
Charité – Universitätsmedizin Berlin
Institute of Virology
Charitéplatz 1
10117 Berlin
Germany
Phone: +49 30 450 625461
Rasche et al.: Highly diversified shrew hepatitis B viruses corroborate ancient origins and divergent infection patterns of mammalian hepadnaviruses
DOI: 10.1073/pnas.1908072116
https://doi.org/10.1073/pnas.1908072116
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