Professor of Molecular Virology
Hypoxic and circadian regulation of viruses
Our research focuses on understanding the role of oxygen and circadian signalling pathways in the regulation of virus infection and how this influences viral tropism and disease pathogenesis. Chronic viral infection of the liver is a global health problem, with over 500 million individuals infected with hepatitis B (HBV) or C (HCV) viruses that cause progressive liver disease that can develop into hepatocellular carcinoma. The low oxygen environment of the liver promotes HBV replication via hypoxia inducible transcription factor (HIFs) binding the viral genome and activating transcription. We are actively studying the role of other oxygenases in regulating host susceptibility to virus infection.
Oxygen tension can vary at different anatomical sites and this can impact viral replication and tropism. For example, immune cells encounter variable oxygen tensions as they migrate from the periphery into tissue and are a major reservoir for HIV infection. We found that HIFs supress HIV transcription and a low oxygen environment favors viral latency. Recent studies during the COVID-19 pandemic highlight a role for HIFs and HIF-mimetic drugs to supress SARS-CoV-2 replication in lung epithelial cells. Our research shows that HIFs can act as a rheostat to determine viral replication and tropism. Pharmaceutical agents that modulate HIF activity provide new therapeutic targets for treating viral infections and associated pathologies.
The circadian clock controls many aspects of mammalian physiology and orchestrates the daily oscillations of biological processes and behavior. An endogenous central clock in the brain synchronizes with clocks in peripheral tissues and regulates our immune system and outcome to viral infections. Our laboratory discovered a role for the circadian transcriptional activator BMAL1 in the regulation of HBV and HCV and more recently SARS-CoV-2. Circadian rhythms can affect the pharmacokinetics and efficacy of therapeutic agents and vaccines, providing fertile ground for the discovery of new antiviral therapies. An increased understanding of the role circadian systems play in virus replication and host immune responses has clinical implications for the management and treatment of viral diseases, highlighting the importance of virus-clock research.
Circadian control of hepatitis B virus replication
Zhuang X. et al, (2021), Nature Communications, 12
Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint
Schmidt NM. et al, (2021), Nature Communications, 12
Supramolecular Cylinders Target Bulge Structures in the 5' UTR of the RNA Genome of SARS-CoV-2 and Inhibit Viral Replication*.
Melidis L. et al, (2021), Angewandte Chemie (International ed. in English), 60, 18144 - 18151
Absolute quantitation of individual SARS-CoV-2 RNA molecules: a new paradigm for infection dynamics and variant differences
Lee JY. et al, (2021)
The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cells.
Zhuang X. et al, (2021), bioRxiv