David Lorne Tyrrell

University of Alberta, Edmonton, Alberta, Canada

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Publications (4)23.02 Total impact

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    ABSTRACT: Immune regulation of cellular metabolism can be responsible for successful responses to invading pathogens. Viruses alter their hosts' cellular metabolism to facilitate infection. Conversely, the innate antiviral responses of mammalian cells target these metabolic pathways to restrict viral propagation. We identified miR-130b and miR-185 as hepatic microRNAs (miRNAs) whose expression is stimulated by 25-hydroxycholesterol (25-HC), an antiviral oxysterol secreted by interferon-stimulated macrophages and dendritic cells, during hepatitis C virus (HCV) infection. However, 25-HC only directly stimulated miR-185 expression, whereas HCV regulated miR-130b expression. Independently, miR-130b and miR-185 inhibited HCV infection. In particular, miR-185 significantly restricted host metabolic pathways crucial to the HCV life cycle. Interestingly, HCV infection decreased miR-185 and miR-130b levels to promote lipid accumulation and counteract 25-HC's antiviral effect. Furthermore, miR-185 can inhibit other viruses through the regulation of immunometabolic pathways. These data establish these microRNAs as a key link between innate defenses and metabolism in the liver.
    No preview · Article · Oct 2015 · Nature Chemical Biology
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    ABSTRACT: Cell death-inducing DFF45-like effector B (CIDEB) is an apoptotic host factor, which was recently found to also regulate hepatic lipid homeostasis. Herein we delineate the relevance of these dual roles of CIDEB in apoptosis and lipid metabolism in the context of the hepatitis C virus (HCV) replication. We demonstrate that HCV up-regulates CIDEB expression in human serum (HS) differentiated hepatoma cells. CIDEB overexpression inhibits HCV replication in HCV replicon expressing Huh7.5 cells, while siRNA knockdown of CIDEB expression in HS differentiated hepatoma cells promotes HCV replication and secretion of viral proteins. Furthermore, we characterize a CIDEB mutant, KRRA, which is deficient in lipid droplet (LD) clustering and fusion and demonstrate that CIDEB-mediated inhibition of HCV is independent of the protein's LD fusogenic role. Our results suggest that higher levels of CIDEB expression, which favour an apoptotic role for the host factor, inhibit HCV. Collectively, our data demonstrate that CIDEB can act as an anti-HCV host factor, and contribute to altered triglyceride homeostasis. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2014 · FEBS Journal
  • Li Zhao · David Lorne Tyrrell
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    ABSTRACT: Abstract Myeloid dendritic cells (mDCs) are the most potent professional antigen-presenting cells that regulate specific T-cell responses. Here we studied the ability of mDCs to kill T cells during HCV infection. We found that mDCs from chronic hepatitis C (CHC) patients expressed upregulated levels of two inhibitory ligands, Fas ligand and the ligand 2 of PD-1 (PD-L2), compared to healthy mDCs. However, their expression of the ligand 1 of PD-1 (PD-L1), tumor necrosis factor-related apoptosis inducing ligand (TRAIL), and B lymphocyte stimulator (BLyS) on the cell surface was comparable to healthy mDCs. CHC patient mDCs had cytotoxic effects on autologous patient T cells and allogeneic healthy T cells. CHC patient T cells had increased expression of PD-1 compared to healthy T cells. These results indicate that the cytotoxic activity of mDCs is upregulated to kill T cells during chronic HCV infection, which represents a novel mechanism of HCV immune evasion.
    No preview · Article · Feb 2013 · Viral immunology
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    ABSTRACT: Hepatitis C virus (HCV) relies on many interactions with host cell proteins for propagation. Successful HCV infection also requires enzymatic activity of host cell enzymes for key post-translational modifications. To identify such enzymes, we have applied activity-based protein profiling to examine the activity of serine hydrolases during HCV replication. Profiling of hydrolases in Huh7 cells replicating HCV identified CES1 (carboxylesterase 1) as a differentially active enzyme. CES1 is an endogenous liver protein involved in processing of triglycerides and cholesterol. We observe that CES1 expression and activity were altered in the presence of HCV. The knockdown of CES1 with siRNA resulted in lower levels of HCV replication, and up-regulation of CES1 was observed to favor HCV propagation, implying an important role for this host cell protein. Experiments in HCV JFH1-infected cells suggest that CES1 facilitates HCV release because less intracellular HCV core protein was observed, whereas HCV titers remained high. CES1 activity was observed to increase the size and density of lipid droplets, which are necessary for the maturation of very low density lipoproteins, one of the likely vehicles for HCV release. In transgenic mice containing human-mouse chimeric livers, HCV infection also correlates with higher levels of endogenous CES1, providing further evidence that CES1 has an important role in HCV propagation.
    Preview · Article · Aug 2010 · Journal of Biological Chemistry