Nucleic Acid-Induced Signaling in Chronic Viral Liver Disease

Abstract

A hallmark for the development and progression of chronic liver diseases is the persistent dysregulation of signaling pathways related to inflammatory responses, which eventually promotes the development of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The two major etiological agents associated with these complications in immunocompetent patients are hepatitis B virus (HBV) and hepatitis C virus (HCV), accounting for almost 1.4 million liver disease-associated deaths worldwide. Although both differ significantly from the point of their genomes and viral life cycles, they exert not only individual but also common strategies to divert innate antiviral defenses. Multiple virus-modulated pathways implicated in stress and inflammation illustrate how chronic viral hepatitis persistently tweaks host signaling processes with important consequences for liver pathogenesis. The following review aims to summarize the molecular events implicated in the sensing of viral nucleic acids, the mechanisms employed by HBV and HCV to counter these measures and how the dysregulation of these cellular pathways drives the development of chronic liver disease and the progression toward HCC.

Toll- like receptor 2 polymorphism and IL-6 profile in relation to disease progression in chronic HBV infection: a case control study in Egyptian patients

“…The present study exhibited remarkable associations between IL-6 levels with evidence of HBV-related disease severity including ALT, AST, advanced fibrosis stage, increased Child Pugh score, and lower platelet count. It was formerly stated for CHB patients, IL-6 levels were significantly higher in patients with severe compared those with mild to moderate inflammation as well as the healthy control groups; besides, IL-6 showed a positive correlation with ALT, AST and TBIL as indicators of liver function, so, they documented that the level of serum IL-6 was closely related to the degree of necrosis of liver cells [ 11 ]. Similar results were also reported regarding the correlations of IL-6 levels with biochemical markers of liver disease [ 34 , 35 ] reflecting its role in evaluating the degree of activity of the inflammatory process in the liver.…”

“…The clinical relevance of TLR signaling has been highlighted by the identification of single nucleotide polymorphisms (SNPs) associated with the clinical course of chronic HBV infection [ 11 ]. The effects of TLRs gene variants in HBV-related liver disease are not well understood.…”

The cGAS-STING Pathway: Novel Perspectives in Liver Diseases

“…However, tumor-derived cGAMP triggered natural killer (NK) cell response and inhibited tumor growth by activating the STING pathway ( 110 ). Although the STING agonists have shown promising results in HBV/HCV infection and HCC therapy in disease models ( 50 , 51 , 91 , 111 ), more preclinical studies and early-stage clinical trials are needed to verify these encouraging survival and safety data.…”

Beyond the Usual Suspects: Hepatitis E Virus and Its Implications in Hepatocellular Carcinoma

“…Chronic inflammation as a result of persistent viral infection is characterized by ongoing cell death and long-term local infiltration of inflammatory cells (e.g., macrophages, mast cells, neutrophils, T- and B-lymphocytes) [ 66 ]. During the active immune response, the cellular microenvironment is highly altered owing to a great abundance of highly reactive oxygen and nitrate species (ROS and RNS), cytokines, chemokines and growth factors [ 88 ]. NK-cells and T-cells releasing a great amount of ROS and RNS lead to increased oxidative stress, which in turn, can cause DNA damage and mutations via DNA modifications or protein damage to DNA repair enzymes and caspases inducing oncogenic mutations and epigenetic modifications (reviewed in [ 89 , 90 ]).…”