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  • Zebularine sale br Authors contribution br Funding sources T

    2022-01-15


    Authors' contribution
    Funding sources This study was supported by CDC intramural funding. Publication costs are funded by an internal program of CDC. MAT was supported by funds from the Association of Public Health Laboratories and CDC (APHL–CDC) Bioinformatics Fellowship Program.
    Competing interests/disclosure
    Availability of data and materials Data is available upon request. Software program is being developed for use to authenticated users of the Global Hepatitis Outbreak and Surveillance Technology (GHOST) at https://webappx.cdc.gov/GHOST/.
    Acknowledgments
    Introduction Infection with hepatitis c virus (HCV) is an important cause of hepatocellular cancer (HCC) and it is currently estimated that 71 million people are chronically infected with HCV (Collaborators POH, 2017). Infection is associated with progressive fibrosis and loss of liver function. Cirrhosis develops in approximately 20–30% of infections and in these individuals there is a 1–7% annual risk of developing HCC (Fattovich et al., 2004). The mechanisms underlying this progression to severe disease are still incompletely understood, but many molecular mechanisms have been proposed. Viral factors including HCV genotype and viral load influence progression (Kanwal et al., 2014). Co-infection with hepatitis B virus (HBV) (Zampino et al., 2015) and environmental factors such as alcohol consumption increase the risk of developing HCC (Donato et al., 2002). Host genetic factors may also influence progression. A recent systematic review (Walker et al., 2018) indicated significant associations between HCC and seventeen host genes in HCV infections, however only weak associations could be made between individual single nucleotide polymorphisms (SNPs) and HCC. Fibrosis and development of HCC are closely linked to altered innate immune signalling during chronic HCV infection (Arzumanyan et al., 2013). Chronic inflammation is known to trigger activation of liver-resident stellate Zebularine sale (reviewed in (Weiskirchen and Tacke, 2014)), differentiating into collagen-producing myofibroblasts. Activation by protease cleavage of PAR 1 results in production of extracellular matrix (ECM) and initiation of fibrosis (Fiorucci et al., 2004). One of the major triggers of stellate cell activation is the action of mannose binding lectin (MBL)-associated serine proteases (MASPs) (Saeed et al., 2013), enzymes associated with the pattern recognition receptors (PRRs) MBL, CL-11, ficolin-2 and ficolin-3. Binding of these PRRs to viruses is well described (Brown et al., 2010, Hamed et al., 2014, Hansen et al., 2010, Pan et al., 2012, Verma et al., 2012) and increased activity of MASPs is associated with development of liver fibrosis (Brown et al., 2007). MBL, ficolin-2 and ficolin-3 are predominantly expressed in the liver but regulation of their expression is still not completely understood, although they are believed to be expressed constitutively, with acute-phase responses observed in only few individuals (Dean et al., 2005). The contribution of MBL to disease progression in HCV infection has been investigated, and MBL polymorphisms have been associated with fibrosis (Alves Pedroso et al., 2008, Koutsounaki et al., 2008). The impact of genetic polymorphisms in the collagen domain of MBL with progression to HCC is still unclear (Eurich et al., 2011, Segat et al., 2008). However, no studies have compared the expression of both MBL and ficolins in patients with different outcomes disease progression. Chronic HCV infection induces liver damage, which may disrupt its ability to synthesise these lectins, thus potentially impairing the anti-viral immune response in later stages of infection. In chronic HBV infection, HCC has been associated with reduced ficolin-2 expression (Chen et al., 2015, Hoang et al., 2011). To investigate the hypothesis that altered PRR activity is associated with development of HCC in chronic HCV infection we studied the activity of MBL, ficolin-2 and ficolin-3 in individuals infected with HCV who experienced different disease endpoints. Assays measuring binding of MBL, ficolin-2 or ficolin-3 to reference ligands were used to determine PRR activity in different individuals. Given that it is clinically important to understand which HCV-infected individuals are most likely to progress to developing hepatocellular carcinoma, we also investigated the possibility that serum PRRs are elevated prior to diagnosis of cancer.