Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling.

Gesche Gerresheim,Oliver Rossbach,Audrey Michel,Pan Hu,Stephen Kiniry,Dieter Glebe,Ivan Shatsky,Pavel Baranov,Manja Marz,Lyudmila Shalamova,Jochen Bathke,Markus Fricke,Michael Niepmann,Dmitri Andreev,Alexander Goesmann

doi:10.3390/ijms20061321

Abstract

Background: Hepatitis C virus (HCV) infects human liver hepatocytes, often leading to liver cirrhosis and hepatocellular carcinoma (HCC). It is believed that chronic infection alters host gene expression and favors HCC development. In particular, HCV replication in Endoplasmic Reticulum (ER) derived membranes induces chronic ER stress. How HCV replication affects host mRNA translation and transcription at a genome wide level is not yet known. Methods: We used Riboseq (Ribosome Profiling) to analyze transcriptome and translatome changes in the Huh-7.5 hepatocarcinoma cell line replicating HCV for 6 days. Results: Established viral replication does not cause global changes in host gene expression—only around 30 genes are significantly differentially expressed. Upregulated genes are related to ER stress and HCV replication, and several regulated genes are known to be involved in HCC development. Some mRNAs (PPP1R15A/GADD34, DDIT3/CHOP, and TRIB3) may be subject to upstream open reading frame (uORF) mediated translation control. Transcriptional downregulation mainly affects mitochondrial respiratory chain complex core subunit genes. Conclusion: After establishing HCV replication, the lack of global changes in cellular gene expression indicates an adaptation to chronic infection, while the downregulation of mitochondrial respiratory chain genes indicates how a virus may further contribute to cancer cell-like metabolic reprogramming (“Warburg effect”) even in the hepatocellular carcinoma cells used here.

Highlights

Hepatitis C Virus (HCV) causes liver disease by preferentially infecting human liver hepatocytes [1]
Even though the use of Huh-7.5 hepatocarcinoma cells in our study already comes with the limitation that we could not observe a full change from primary liver hepatocyctes to hepatocellular carcinoma (HCC) cells, our results show the upregulation of genes involved in Endoplasmic Reticulum (ER) stress, autophagy, metabolic reprogramming and further contribution to
Our results shown here support the idea that downregulation of mitochondrial respiratory chain activity upon active Hepatitis C virus (HCV) replication in the cells may further contribute to the Warburg effect, even though the Huh-7.5 cell line used here already is a hepatocarcinoma cell line

Summary

Introduction

Hepatitis C Virus (HCV) causes liver disease by preferentially infecting human liver hepatocytes [1]. About 71 million people are chronic carriers of HCV, of which about 15–30% develop liver cirrhosis within 20 years [2,3], which may lead to hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) infects human liver hepatocytes, often leading to liver cirrhosis and hepatocellular carcinoma (HCC). Conclusion: After establishing HCV replication, the lack of global changes in cellular gene expression indicates an adaptation to chronic infection, while the downregulation of mitochondrial respiratory chain genes indicates how a virus may further contribute to cancer cell-like metabolic reprogramming (“Warburg effect”) even in the hepatocellular carcinoma cells used here

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Conclusion