Hepatitis C virus (HCV) is a major cause of global morbidity, causing long-term pathologies, including cirrhosis and hepatocellular carcinoma. While hepatocytes are the major site of viral replication, the liver contains multiple non-parenchymal cells that regulate the hepatic microenvironment and may affect HCV infection in vivo. Current understanding of the role of non-parenchymal cells in HCV infection is limited. Therefore, this project aimed to establish co-culture systems that allowed investigations into interactions between hepatocytes and non-parenchymal cells, and how these interactions affected HCV infection. The results showed that in co-culture, activated liver myofibroblasts (aLMFs) negatively regulate HCV entry, replication and spread of infection in a cell contact dependent manner. Soluble factors, including extracellular matrix proteins, and common antiviral pathways did not induce this effect. Instead, we found that aLMFmodulated cell-contact affected hepatocyte membrane receptor dynamics, reducing the mobility of the HCV receptor, CD81, impairing viral entry and replication. In addition, we found that aLMF surface expressed VAP-1 also significantly reduced virus infection independently of receptor modulation. These findings greatly improved our understanding of how the interactions between hepatic cells affect HCV, highlighting the importance of non-parenchymal cells in mediating infection in the liver microenvironment.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:659158 |
| Date | January 2015 |
| Creators | Galsinh, Sukhdeep Kaur |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/6109/ |
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