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Hepatitis C Virus Infection and Intrinsic Disorder in the Signaling Pathways Induced by Toll-Like Receptors

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Human hepatitis C virus causes contagious liver disease hepatitis C, which is broadly spread around the globe. Infection with this virus causes an inflammation of the liver that leads to both acute and chronic hepatitis, which, if left untreated, often results in the development of serious lifelong illnesses such as liver fibrosis, liver cirrhosis, hepatocellular carcinoma, and end-stage liver disease in humans. Toll-like receptors are a class of pattern recognition receptors that exist in liver parenchymal cells and various immune cells, and play an important role in the liver immune system by initiating multiple cellular downstream pathways in response to the recognition of pathogens such as hepatitis C virus. Proteins from the hepatitis C virus, Toll-like receptors themselves, and proteins from the pathways they activate are multifunctional. Since protein multifunctionality is commonly associated with intrinsic disorder (i.e., lack of stable 3D structures), we used an intrinsic disorder angle to examine the interplay between the hepatitis C virus infection and signaling pathways induced by Toll-like receptors. We show that almost all of these proteins contained noticeable levels of disorder, indicating that intrinsic disorder is prominently utilized in virus–host warfare.

Abstract

In this study, we examined the interplay between protein intrinsic disorder, hepatitis C virus (HCV) infection, and signaling pathways induced by Toll-like receptors (TLRs). To this end, 10 HCV proteins, 10 human TLRs, and 41 proteins from the TLR-induced downstream pathways were considered from the prevalence of intrinsic disorder. Mapping of the intrinsic disorder to the HCV-TLR interactome and to the TLR-based pathways of human innate immune response to the HCV infection demonstrates that substantial levels of intrinsic disorder are characteristic for proteins involved in the regulation and execution of these innate immunity pathways and in HCV-TLR interaction. Disordered regions, being commonly enriched in sites of various posttranslational modifications, may play important functional roles by promoting protein–protein interactions and support the binding of the analyzed proteins to other partners such as nucleic acids. It seems that this system represents an important illustration of the role of intrinsic disorder in virus–host warfare.

SUBMITTER: Redwan E

PROVIDER: S-EPMC9312352 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Woodchucks infected with woodchuck hepatitis virus (WHV) represent a highly valuable model of human hepatitis B virus (HBV) infection, chronic hepatitis (CH), and virus induced-primary liver cancer. Toll-like receptors (TLRs) are important mediators of immune responses playing pivotal roles in the pathogenesis of viral diseases; however, their expression profiles in different forms of infection and stages of hepatitis, and in healthy animals remain essentially unknown. In this study, woodchuck TLRs 1-10 exon fragments were identified and TLR genes transcription quantified in livers, primary hepatocytes, peripheral blood mononuclear cells (PBMC), and in selected organs during experimental WHV infection. Among others, liver biopsies from acute hepatitis (AH) and CH showed significantly augmented expression of the majority of TLRs when compared to healthy and woodchucks prior to AH, with resolved AH or primary occult infection. In contrast to the liver tissue, significant upregulation of TLR3, TLR4, and TLR10, but downregulation of TLR7, characterized hepatocytes derived from livers of animals with resolved AH accompanied by secondary occult infection. Hepatocytes from CH showed significantly lower expression or a trend toward suppression of several TLRs when compared to hepatocytes from healthy animals and woodchucks with other forms of infection or hepatitis, suggesting that hepatocyte innate immune response is downregulated during CH. Contrastingly, upregulated transcription of some TLRs characterized PBMC throughout CH. Our study uncovered that TLR expression significantly varies between different forms of hepadnaviral infection and whether infection is accompanied or not by hepatitis. The results showed that the profiles of TLRs' expression in circulating lymphomononuclear cells do not mirror accurately those of livers and hepatocytes from infected animals. These findings are of importance to the understanding of immune process operating at different sites targeted by virus in the course of hepadnaviral infection and evaluation of future therapies modifying antiviral innate responses in the woodchuck model.

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Hepatitis C Virus Infection and Intrinsic Disorder in the Signaling Pathways Induced by Toll-Like Receptors

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