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Hepatitis C virus alters the morphology and function of peroxisomes.

ABSTRACT: Despite the introduction of effective treatments for hepatitis C in clinics, issues remain regarding the liver diseases induced by chronic hepatitis C virus (HCV) infection. HCV is known to disturb the metabolism of infected cells, especially lipid metabolism and redox balance, but the mechanisms leading to HCV-induced pathogenesis are still poorly understood. In an APEX2-based proximity biotinylation screen, we identified ACBD5, a peroxisome membrane protein, as located in the vicinity of HCV replication complexes. Confocal microscopy confirmed the relocation of peroxisomes near HCV replication complexes and indicated that their morphology and number are altered in approximately 30% of infected Huh-7 cells. Peroxisomes are small versatile organelles involved among other functions in lipid metabolism and ROS regulation. To determine their importance in the HCV life cycle, we generated Huh-7 cells devoid of peroxisomes by inactivating the PEX5 and PEX3 genes using CRISPR/Cas9 and found that the absence of peroxisomes had no impact on replication kinetics or infectious titers of HCV strains JFH1 and DBN3a. The impact of HCV on peroxisomal functions was assessed using sub-genomic replicons. An increase of ROS was measured in peroxisomes of replicon-containing cells, and this increase was more pronounced than in mitochondria or the cytosol, suggesting that the redox balance of peroxisomes is specifically impaired in cells replicating HCV. Our study provides evidence that peroxisome function and morphology are altered in HCV-infected cells.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Huh-7 Cell

DISEASE(S): Hepatitis C

SUBMITTER: SALIOU Jean-Michel

LAB HEAD: Jean-Michel Saliou

PROVIDER: PXD044994 | Pride | 2023-10-24

REPOSITORIES: Pride

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Hepatitis C virus alters the morphology and function of peroxisomes.

Martin de Fourchambault Esther E Callens Nathalie N Saliou Jean-Michel JM Fourcot Marie M Delos Oceane O Barois Nicolas N Thorel Quentin Q Ramirez Santseharay S Bukh Jens J Cocquerel Laurence L Bertrand-Michel Justine J Marot Guillemette G Sebti Yasmine Y Dubuisson Jean J Rouillé Yves Y

Frontiers in microbiology 20230921

Despite the introduction of effective treatments for hepatitis C in clinics, issues remain regarding the liver disease induced by chronic hepatitis C virus (HCV) infection. HCV is known to disturb the metabolism of infected cells, especially lipid metabolism and redox balance, but the mechanisms leading to HCV-induced pathogenesis are still poorly understood. In an APEX2-based proximity biotinylation screen, we identified ACBD5, a peroxisome membrane protein, as located in the vicinity of HCV re ...[more]

PMID: 37808318

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Project description:Hepatitis C virus (HCV) is a global problem. To better understand HCV infection researchers employ in vitro HCV cell-culture (HCVcc) systems that use Huh-7 derived hepatoma cells that are particularly permissive to HCV infection. A variety of hyper-permissive cells have been subcloned for this purpose. In addition, subclones of Huh-7 which have evolved resistance to HCV are available. However, the mechanisms of susceptibility or resistance to infection among these cells have not been fully determined. In order to elucidate mechanisms by which hepatoma cells are susceptible or resistant to HCV infection we performed genome-wide expression analyses of six Huh-7 derived cell cultures (Huh-7, Huh-7.5.1, Huh-7.5.1c2, R1.09, R1.10 and R2.1) R that have different levels of permissiveness to infection. A great number of genes, representing a wide spectrum of functions are differentially expressed between cells. To focus our investigation, we identify host proteins from HCV replicase complexes, perform gene expression analysis of three HCV infected cells (infected Huh-7, Huh-7.5.1 and Huh-7.5.1c2) and conduct a detailed analysis of differentially expressed host factors by integrating a variety of data sources. Our results demonstrate that changes relating to susceptibility to HCV infection in hepatoma cells are linked to the innate immune response, secreted signal peptides and host factors that have a role in virus entry and replication. This work identifies both known and novel host factors that may influence HCV infection. Our findings build upon current knowledge of the complex interplay between HCV and the host cell, which could aid development of new antiviral strategies. Six Huh-7 derived hepatoma cell types that have different levels of susceptibility to HCV infection in cell culture are used: Huh-7, Huh-7.5.1, Huh-7.5.1c2, R1.09, R1.10 and R2.1. Of these the first three (label starting Huh are susceptible to HCV infection and the latter three (label starting R are resistant to HCV infection. All cell types are derived from Huh-7. Huh-7.5.1 is a subclone of Huh-7.5 that in turn is a subclone of Huh-7. Huh-7.5.1c2 is a subclone of Huh-7.5.1. R1.09 and R1.10 are subclones of R1 that is inturn a sublone of Huh-7.5,1. R2.1 is a subclone of Huh-7.5.1. 39 samples are used. In every case there are 3 biological replicates, i.e., there are 13 unique conditions (39/3=13). These samples are subdivided between two studies: (1) A comparison of HCV infection resistant cells R1.09, R1.10 and R2 against HCV susceptible Huh-7.5.1. (2) A comparison of JFH1 HCV infected Huh-7, Huh-7.5.1 and Huh-7.5.1c2 cells versus their uninfected counterparts. In each case there are two uninfected counterparts, cells that were harvested after being in culture for 20 hours and cells that were harvested at the same time point as the infected cells, that is, at the peak time of infection. Peak times for infection vary between cells, depending on their susceptibility to infection: 168 hours for Huh-7, 120 hours for Huh-7.5.1 and 96 hours for Huh-7.5.1c2.

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Dataset Information

Hepatitis C virus alters the morphology and function of peroxisomes.

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Publications

Hepatitis C virus alters the morphology and function of peroxisomes.

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