Transcriptional Dysregulation of Upstream Signaling of IFN Pathway in Chronic HCV Type 4 Induced Liver Fibrosis

Abstract

IFN orchestrates the expression of various genes to halt hepatitis C virus (HCV) replication with the possibility of either reduced or increased liver fibrosis; due to controlled viral replication or overproduction of inflammatory mediators, repectively. In this study, we examined the transcriptional profiling of type I IFN related genes in HCV-chronically infected patients with varying degrees of liver fibrosis. PCR array was used to examine the expression of 84 type I IFN related genes in peripheral blood mononuclear cells (PBMCs) RNA from 12 treatment-naïve chronic HCV patients (5 F0-F1 and 7 F2-F4) and 5 healthy subjects. We further validated our results by quantitative real time PCR (qRT-PCR) in 103 treatment-naïve chronic HCV patients (43 F0-F1 and 60 F2-F4) and 15 controls. PCR array data revealed dysregulation in TLR7 pathway. The expression of TLR7 was decreased by 4 folds and MyD88 was increased by 3 folds in PBMCs of F2-F4 patients when compared to the healthy volunteers (p = 0.03 and 0.002, respectively). In addition, IRF7 and TLR7 showed dramatic downregulation (6 and 8 folds, respectively) in F2-F4 patients when compared to F0-F1 ones. qRT-PCR confirmed the altered expression patterns of TLR7 and MyD88 in F2-F4 patients when compared to either controls or F0-F1 patients. However, by qRT-PCR, IRF7 and NF-κB1 (TLR7 pathway transcription factors) exhibited similar mRNA abundance among F2-F4 and F0-F1 patients. These results suggest that TLR7 and MyD88 are possible candidates as biomarkers for the progression of HCV-induced liver fibrosis and/ or targets for therapeutic intervention.

Hepatitis C virus–induced CCL5 secretion from macrophages activates hepatic stellate cells

“…The World Health Organization estimates that approximately 150 million people have chronic hepatitis C virus (HCV) infection worldwide . A significant number of chronically infected people will develop a potentially life‐threatening problem, such as liver fibrosis, cirrhosis, and hepatocellular carcinoma . Approximately 700,000 people die each year from HCV‐related liver diseases .…”

“…(1) A significant number of chronically infected people will develop a potentially life-threatening problem, such as liver fibrosis, cirrhosis, and hepatocellular carcinoma. (2) Approximately 700,000 people die each year from HCV-related liver diseases. (3) Advanced hepatic fibrosis including cirrhosis is the primary lesion in most cases of hepatocellular carcinoma.…”

Correlation between IL28B/TLR4 genetic variants and HCC development with/without DAAs treatment in chronic HCV patients

“… 10 Our previous studies confirmed that the genetic variants dramatically orchestrate the mRNA expression of ISGs which are the master players of innate immunity against HCV burden. 37 , 38 , 39 , 40 The study by Poordad et al, (2012) highlighted the A >1 log 10 decline in HCV RNA at the fourth week of therapy is the premier predictor of a SVR, regardless of both polymorphisms in IL-28B (rs12979860 and rs8099917). 41 …”