Determinants for severe outcomes of hepatitis E acquired in Switzerland

Background: Hepatitis E virus (HEV), a positive-strand RNA virus, is believed to be the most common cause of acute hepatitis and jaundice in the world. Several HEV genotypes (gt) can infect humans, including the gt 1 and 2 found in developing countries and the zoonotically-transmitted gt 3 and 4 present in industrialized regions. The latter genotypes, transmission occurs primarily through the consumption of raw or undercooked meat but other routes have been described, including transmission through blood products. Most HEV infections are asymptomatic but, in some instances, it may lead to severe hepatitis, including fatal course, or extrahepatic manifestations such as neurological symptoms. Furthermore, while HEV infection is usually self-resolved, it may persist in immunocompromised patients and cause chronic liver disease. In Switzerland, it is estimated that the seroprevalence of HEV reaches about 20% in the general population. Therefore, hepatitis E represents a growing global health concern. Specific aim: Within the framework of this grant proposal, we shall obtain the full-length sequence of viral isolates from selected infected patients with various clinical presentation, including those with severe course, to identify determinants for these extreme phenotypes.Experimental design and methods: The experiments proposed in this grant application build on a collaborative effort of clinicians and virologists. Our common efforts shall involve selection of the samples and analysis of the clinical parameters of the patients, analysis of the viral isolates by next generation sequencing (NGS), constructions of full-length and subgenomic replicon HEV constructs including their phenotypic characterization in cell culture.Expected value of the proposed project: The proposed project should yield important insights into the viral determinants for severe outcomes of hepatitis E acquired in Switzerland. These collective efforts shall allow to establish a sequencing and analysis pipeline to monitor and genotype as well as to phenotype HEV strains responsible of infections in Switzerland for future prospective studies.