Zoonotic potential of rat hepatitis E virus in Germany

Infections with the hepatitis E virus (HEV) can lead to acute hepatitis in humans. In transplantation patients, chronic hepatitis frequently occurs, which often leads to a life-threatening liver cirrhosis. The number of notified hepatitis E cases in Germany has been continuously increased in the last years. Here, the HEV genotype 3 (GT3) is mainly found, which is distributed in pigs and can be transmitted zoonotically to humans. An additional HEV (ratHEV) was discovered a few years ago, which is worldwide distributed in various rat species. RatHEV is only distantly related to HEV-GT3. However, since 2018, ratHEV has also been detected in several human hepatitis patients, mainly in Hongkong. The aim of the project is the assessment of the zoonotic potential of ratHEV, its circulation in rats and the transmission of the agent to humans in Germany. To this end, several investigations will be performed by an interdisciplinary team of physicians, veterinarians and biologists in this PhD project. Hepatitis patients, blood donors and rat samples from Germany will be investigated to unravel the level of current ratHEV circulation. In addition, the infectivity and pathogenicity of a human ratHEV strain from Hongkong will be compared to that of a strain derived from a rat from Germany and an HEV-GT3 strain. The investigations should show, if ratHEV is actually present in humans and rats in Germany and clarify, if the zoonotic potential of strains from Germany is similar to that from Hongkong. The results should therefore contribute to clarify the zoonotic potential of a novel agent, which possibly is just about to jump from animals to humans.

The rat hepatitis E virus (ratHEV) was discovered in 2010 in Norway rats in Germany. Subsequently, it was shown to be distributed in various rat species worldwide. In 2018, ratHEV was shown to infect humans and lead to liver inflammation for the first time. At the beginning of the project, several cases of hepatitis in patients from Hong Kong and a single case from Canada were described. In contrast, the significance of ratHEV as a causative agent of human disease in Germany and Europe was still unclear. The distinct transmission routes of the virus were also largely unknown.The aim of the project was therefore to investigate the potential of ratHEV strains occurring in Germany to infect humans, to determine the circulation of the virus in wild rat populations and to identify its possible transmission to humans, including the induction of disease. The results should also generally contribute to the characterization of a new pathogen that potentially starts to spread from animals to humans.The project was carried out by an interdisciplinary team of physicians, veterinarians and biologists. Studies on wild rats in a large city of Germany showed that ratHEV could be detected actually and in samples more than 10 years old, indicating continuous circulation of the virus in the rat population. RatHEV strains from a rat from Germany and from a human patient from Hong Kong could be propagated in the laboratory and compared to each other. Despite obvious genetic differences, both strains showed efficient growth in cultures of human liver carcinoma cells. Studies in a humanized animal model, which can better reflect the human liver than cell cultures, are still ongoing. Investigations of patient samples from Germany lead to detection an infection with ratHEV in one case. The patient, who had an underlying oncological disease, had symptoms of hepatitis at the time of detection. A PCR test was developed for the automated detection of ratHEV in human samples, which showed good  results in all parameters examined.The results show that ratHEV is present in wild rats in Germany and that these animals or their excretions have to be regarded as a source of infection for humans. The virus strains circulating in these rats showed the ability to efficiently infect human cells in the laboratory, which indicates a general transmissibility to humans. This is also supported by the detection of a ratHEV infection in a hepatitis patient in Germany. The automated PCR test developed here can be used in future for the rapid identification of ratHEV infections in humans.Generally, the reaults of the project indicate that the ratHEV strains circulating in Germany can also infect humans and cause disease. Wild rat populations, which can harbor the virus for a long time, were identified as possible sources of infection. These results and the new laboratory methods developed in the project can help to better understand the properties of this novel virus in the future and to further develop strategies for the early detection and prevention of diseases caused by ratHEV in humans.