Avista Wahid, Nele Meyer, Christine Wundes, Lucas Hüffner, Saskia Janshoff, Nicola Frericks, Martina Friesland, Katja Dinkelborg, Elmira Aliabadi, Fenja Laue, Markus Cornberg, Benjamin Maasoumy, Birgit Bremer, Sven Pischke, Tobias Müller, Julian Zur Schulze Wiesch, Julia Benckert, Rainer G. Ulrich, Svenja Hardtke, Petra Dörge, Florian Vondran, Ansgar Lohse, Michael Peter Manns, Daniel Todt, Heiner Wedemeyer, Thomas Pietschmann, Eike Steinmann, André Gömer, Patrick Behrendt
{"title":"戊型肝炎病毒在肾脏中的肝外复制和基因组特征","authors":"Avista Wahid, Nele Meyer, Christine Wundes, Lucas Hüffner, Saskia Janshoff, Nicola Frericks, Martina Friesland, Katja Dinkelborg, Elmira Aliabadi, Fenja Laue, Markus Cornberg, Benjamin Maasoumy, Birgit Bremer, Sven Pischke, Tobias Müller, Julian Zur Schulze Wiesch, Julia Benckert, Rainer G. Ulrich, Svenja Hardtke, Petra Dörge, Florian Vondran, Ansgar Lohse, Michael Peter Manns, Daniel Todt, Heiner Wedemeyer, Thomas Pietschmann, Eike Steinmann, André Gömer, Patrick Behrendt","doi":"10.1111/liv.70183","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Introduction</h3>\n \n <p>The hepatitis E virus (HEV; species <i>Paslahepevirus balayani</i>) is a common human pathogenic and zoonotic virus that can cause both acute fulminant and chronic hepatitis. Despite its reputation as a hepatotropic virus, HEV infection is also associated with a number of extrahepatic diseases, including kidney disorders. However, the extent to which HEV replicates in kidney cells remains unclear. The present study aims to investigate the capacity of HEV to propagate in kidney cells in vitro and to assess whether HEV displays mutational signatures that correlate with compartmentalisation in vivo.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We use HEV cell culture models to study the replication cycle and the effect of antivirals in human kidney cell lines and primary cells. In addition, we identified patients with chronic HEV infection (<i>n</i> = 9) from which we then sequenced the viral RNA of urine, stools and plasma to analyse the viral sequence composition, to assess intra-host diversity and compartmentalisation (<i>n</i> = 2).</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>A wide range of human kidney cell lines as well as primary cells supports viral entry, replication and propagation of HEV in vitro. Interestingly, the broad-spectrum antiviral ribavirin was less effective in inhibiting HEV replication in some kidney cells. Sequencing of HEV RNA-directed RNA polymerase coding region from plasma, stool and urine and subsequent phylogenetic analysis revealed diversification of HEV into tissue-specific viral subpopulations. In particular, the viruses derived from urine were found to be distinct from those derived from plasma and stool.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>In conclusion, kidney cells support the propagation of HEV in vitro and exhibit reduced sensitivity to antiviral treatment. Furthermore, HEV patient-derived sequences demonstrated compartmentalisation into distinct clusters that correlated with sample source. Collectively, these data indicate the potential for extrahepatic replication of HEV, which may result in clinically significant disease or serve as a reservoir for patient relapse.</p>\n \n <p><b>Trial Registration:</b> HepNet-SofE study (NCT03282474)</p>\n </section>\n </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 7","pages":""},"PeriodicalIF":5.2000,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70183","citationCount":"0","resultStr":"{\"title\":\"Extrahepatic Replication and Genomic Signatures of the Hepatitis E Virus in the Kidney\",\"authors\":\"Avista Wahid, Nele Meyer, Christine Wundes, Lucas Hüffner, Saskia Janshoff, Nicola Frericks, Martina Friesland, Katja Dinkelborg, Elmira Aliabadi, Fenja Laue, Markus Cornberg, Benjamin Maasoumy, Birgit Bremer, Sven Pischke, Tobias Müller, Julian Zur Schulze Wiesch, Julia Benckert, Rainer G. 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The present study aims to investigate the capacity of HEV to propagate in kidney cells in vitro and to assess whether HEV displays mutational signatures that correlate with compartmentalisation in vivo.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>We use HEV cell culture models to study the replication cycle and the effect of antivirals in human kidney cell lines and primary cells. In addition, we identified patients with chronic HEV infection (<i>n</i> = 9) from which we then sequenced the viral RNA of urine, stools and plasma to analyse the viral sequence composition, to assess intra-host diversity and compartmentalisation (<i>n</i> = 2).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>A wide range of human kidney cell lines as well as primary cells supports viral entry, replication and propagation of HEV in vitro. 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Extrahepatic Replication and Genomic Signatures of the Hepatitis E Virus in the Kidney
Introduction
The hepatitis E virus (HEV; species Paslahepevirus balayani) is a common human pathogenic and zoonotic virus that can cause both acute fulminant and chronic hepatitis. Despite its reputation as a hepatotropic virus, HEV infection is also associated with a number of extrahepatic diseases, including kidney disorders. However, the extent to which HEV replicates in kidney cells remains unclear. The present study aims to investigate the capacity of HEV to propagate in kidney cells in vitro and to assess whether HEV displays mutational signatures that correlate with compartmentalisation in vivo.
Methods
We use HEV cell culture models to study the replication cycle and the effect of antivirals in human kidney cell lines and primary cells. In addition, we identified patients with chronic HEV infection (n = 9) from which we then sequenced the viral RNA of urine, stools and plasma to analyse the viral sequence composition, to assess intra-host diversity and compartmentalisation (n = 2).
Results
A wide range of human kidney cell lines as well as primary cells supports viral entry, replication and propagation of HEV in vitro. Interestingly, the broad-spectrum antiviral ribavirin was less effective in inhibiting HEV replication in some kidney cells. Sequencing of HEV RNA-directed RNA polymerase coding region from plasma, stool and urine and subsequent phylogenetic analysis revealed diversification of HEV into tissue-specific viral subpopulations. In particular, the viruses derived from urine were found to be distinct from those derived from plasma and stool.
Conclusions
In conclusion, kidney cells support the propagation of HEV in vitro and exhibit reduced sensitivity to antiviral treatment. Furthermore, HEV patient-derived sequences demonstrated compartmentalisation into distinct clusters that correlated with sample source. Collectively, these data indicate the potential for extrahepatic replication of HEV, which may result in clinically significant disease or serve as a reservoir for patient relapse.
Trial Registration: HepNet-SofE study (NCT03282474)
期刊介绍：
Liver International promotes all aspects of the science of hepatology from basic research to applied clinical studies. Providing an international forum for the publication of high-quality original research in hepatology, it is an essential resource for everyone working on normal and abnormal structure and function in the liver and its constituent cells, including clinicians and basic scientists involved in the multi-disciplinary field of hepatology. The journal welcomes articles from all fields of hepatology, which may be published as original articles, brief definitive reports, reviews, mini-reviews, images in hepatology and letters to the Editor.
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