Development of activation-induced marker assay to identify HCV-specific T cells for single-cell RNA-seq analysis.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE273224 | GEO | 2024/10/30
REPOSITORIES: GEO
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Project description:Little is known on the immune status in liver and blood of chronic HCV patients long after therapy-induced viral clearance. In this study, we demonstrate that 4 years after clearance, regulation of HCV-specific immunity in blood by regulatory T-cells (Treg) and the immunosuppressive cytokines IL-10 and TGF-β is still ongoing. Importantly, sampling of the liver 4 years after clearance shows that intrahepatic Treg are still present in all patients, suggesting that liver T-cells remain regulated. Identifying mechanisms that regulate HCV-specific memory T-cell responses after clearance is highly relevant for the development of protective vaccines, especially in patients at high-risk of reinfection.
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Project description:Development of activation-induced marker assay to identify HCV-specific T cells for single-cell RNA-seq analysis.
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Project description:The main goal of this study is to characterize the transcriptional modulations induced by antiviral compounds derived from chloroquine on Huh7 cells infected with HCV. And thus to identify among the genes modulated by infection, those who are regulated by chloroquine and potentially involved in the antiviral activity of the compound.Two HCV cell models were used: a non-infectious HCV replicon and the infectious HCV cell culture (HCVcc). In addition, this study aimed to highlight the characteristics of derivatives of antiviral chloroquine, compared with chloroquine itself. Abstract from the associated publication: Autophagy is a process of self-degradation of cellular components in which double-membrane autophagosomes sequester organelles or portion of cytosol and fuse with lysosomes or vacuoles for breakdown by resident hydrolases. Autophagy is upregulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation, ER stress, and pathogen infection. Indeed, infection with hepatitis C virus (HCV) was shown to induce autophagy through ER stress signaling and subsequent Unfolded Protein Response (UPR) activation. Moreover, a role of autophagy in promoting HCV infection has been suggested and chloroquine (CQ), a lysosomal protease inhibitor, has been seen blocking autophagy as well as inhibiting HCV replication. In the present report, mechanisms accounting for these inhibitory effects were investigated. Gene expression profiling was performed on CQ treated JFH-1-infected Huh7 cells to identify the host cellular genes that are transcriptionally regulated by infection, and silenced by CQ-based treatment. Herein, we demonstrate that CQ reduces the expression of genes induced by the viral infection such as those encoding autophagic key factors triggering the turn-off of mTOR activity as well as factors involved in p53 and NF-KappaB activities. However, we present several lines of evidence demonstrating that the CQ repressive effect observed on the HCV-induced pathways results from a decrease of ER stress due to the upstream pH-dependent inhibitory effect of CQ on viral replication.
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