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Plenary Lecture 04
A Role for Low Oxygen and Hypoxia Inducible Factors to Regulate Virus Replication and Pathogenesis
Chronic viral infection of the liver is a global health problem, with over 500 million individuals infected with hepatitis C or B viruses (HCV/HBV) that cause liver disease that can progress to hepatocellular carcinoma (HCC): a metastatic cancer with limited therapeutic options. Low oxygen environments, naturally found in the liver, enhance viral replication and this is mediated by hypoxia inducible transcription factors (HIFs) regulating host pathways that are essential for viral replication.
Autotaxin (ATX) is a phospholipase with diverse roles in physiological and pathological processes including inflammation and oncogenesis. Clinical studies show increased ATX expression in chronic viral hepatitis, however, the pathways regulating ATX and its role in the viral life cycle are poorly understood. We demonstrate that low oxygen regulates ATX mRNA levels and hypoxia gene signature analysis of viral associated-HCC show a significant association between ATX expression levels and progressive HCC phenotype. Importantly, inhibiting ATX-lysophosphatidic acid signalling reduced HBV and HCV replication, highlighting a positive role for this phospholipase in the viral life cycle.
HIFs direct extensive transcriptional responses that enable a cell to respond to diverse physiological or pathophysiological signals. Hepatitis B and C viruses activate HIFs and promote a pseudohypoxic state. Current HCC therapies show limited efficacy and recent research efforts have focused on the molecular profiling of tumours to identify gene signatures that predict disease outcome and response to therapy. Understanding how viruses influence host gene transcription is fundamental and profiling HIF-transcriptional targets in infected cells provides a unique opportunity to define the role of HIF in viral-associated HCC heterogeneity and inform stratified approaches for new treatments.
Presenter:
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Jane McKeating, University of Oxford, United Kingdom
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Session Chairs:
Mirjam Zeisel, Inserm U1110, France
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Annette Martin, Institut Pasteur, France
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Plenary Lecture 05
Approaching the Immune System as an Interacting Ensemble of Cells
Diversity in the mammalian immune system is essential for protecting the host against a broad range of threats, and is most clearly evident during dynamic processes such as differentiation and antigenic response. Recent years have witnessed transformative and intersecting advances in nanofabrication and molecular biology that enable deep profiling of low-input samples. Collectively, these afford new and exciting opportunities to study heterogeneity in immune responses, starting from the level of the single cell, with the potential to fundamentally advance our understanding of systems-level immune regulation in health and disease. Illustratively, I will discuss how we can leverage single-cell genomic approaches and, in particular, single-cell RNA-Seq to explore the extensive functional diversity among immune cells, and uncover, from the bottom-up, distinct cell states and their molecular drivers. Finally, I will discuss emerging experimental strategies for achieving the statistical power and control necessary to reconstruct intra- and inter-cellular circuits, enumerate and redefine cell states and types, and transform our understanding of systems-level cellular decision-making on a genomic scale.
Presenter:
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Alex Shalek, Massachusetts Institute of Technology
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Session Chairs:
Shirit Einav, Stanford University
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Judith Gottwein, Copenhagen University Hospital, Denmark
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Poster Removal Hours for Presenters
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Poster Removal Hours for Presenters
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