Combined Analysis of Metabolomes, Proteomes, and Transcriptomes of Hepatitis C Virus–Infected Cells and Liver to Identify Pathways Associated With Disease Development

Abstract

See Covering the Cover synopsis on 271. See editorial on page 300.

Multi-omic Analyses Reveal Complex Interactions Between HCV and Hepatocytes Demonstrating That the Red Queen Is Up and Running

“…HCV infection is detected in the hepatocytes by pattern recognition receptors (PRRs) that induce interferon (INF) responses, thereby triggering interferon stimulated genes (ISGs) specifically targeting and inhibiting viral replication. 5 Indeed, by transcriptome analysis, Lupberger et al, 2 detected mRNA upregulation of genes downstream of the sensors RIG-I, MDA5, TLR3, as has been previously reported in cell culture models and liver biopsies. 5,6 Gene Set Enrichment Analysis (GSEA) following comprehensive mining gene sets from multiples databases uncovered remarkable down regulation of host processes, with matched responses at both the mRNA and protein levels.…”

“…Indeed, the dependency of HCV on lipids in each step of its life cycle, and the consequent manipulation of host lipid metabolism by the virus, is well established. 10 The data presented by Lupberger et al, 2 provide evidence for the role of peroxisome impairment in this process. It also establishes a beneficial impact of increasing glucose metabolism on the virus replication by promoting peroxisome dysfunction and VLCFs accumulation.…”

“…This competition leads to co-evolution of the virus and the host, where each adapts to keep up with an ongoing "arms race", exemplifying the "red queen hypothesis" 1 . In this issue of Gastroenterology, Lupberger et al, 2 present a striking example for this interplay between hepatitis C virus (HCV) and the hepatocyte. HCV is the most common risk factor for hepatocellular carcinoma (HCC) in Western countries, 3 and a major public health problem with over 71 million infected people worldwide.…”

“…In summary, Lupberger et al, 2 provide valuable insights into the mechanisms of HCV immune evasion and HCV-induced progression to steatohepatitis and HCC, which may lead to new targets of preventing liver diseases. This study is an elegant example of how global mechanistic insights can be achieved by integrating transcriptomics, proteomics, metabolomics as well as data mining, providing a multilayered atlas leading to novel information which may not be identified by a single omics approach.…”

“…Multiomics approach identifies molecular mechanisms leading to liver diseases and HCC. The study by Lupberger et al,2 integrated data obtained from cell culture and mouse models for HCV infection, as well as from human liver samplesinduced progression towards fatty liver diseases, NASH and HCC. The directions of the arrows indicate the contribution of each mechanism to liver diseases, and their color indicates their increase (red) or decrease (blue) following HCV infection.…”