We aim to understand and therapeutically exploit early stages of positive-sense RNA virus infection, including entry and virus-induced remodelling of intracellular membranes. We focus on highly conserved virus-host interactions with the ultimate goal of developing broadly acting antivirals. Some of our research questions are as follows:
Glycans as targets for broad spectrum viral attachment inhibitors
Most viruses interact with complex carbohydrates (called glycans) to attach to cells. This primary non-specific attachment involving viral and cellular glycans serves to concentrate viral particles on the surface, facilitating higher-affinity interactions with specific secondary receptors that are required for viral entry. We previously found that certain natural products (including the green tea polyphenol, epigallocatechin gallate) inhibit primary viral attachment to cellular glycans by competing for binding (e.g., Colpitts et al. (2014) J. Virol.). We are currently working to identify which types of glycans mediate coronavirus attachment to allow for the rational design of glycan-mimicking viral attachment inhibitors.
Understanding the role of cellular cyclophilins in positive-sense RNA virus replication
Cyclophilins are cellular proteins that have been implicated in the replication of many positive-sense RNA viruses that are problematic for human health (e.g., hepatitis C virus, dengue virus, Zika viruses, SARS-CoV-1, SARS-CoV-2 and other coronaviruses). Using a combination of genetics and chemical biology approaches, we recently showed that hepatitis C virus uses cyclophilin A to evade cellular innate immune responses (Colpitts et al. (2020) eLife). We are now working to determine the role of cyclophilin A in flavivirus and coronavirus replication to inform our understanding of the antiviral mechanisms of cyclophilin inhibitors, with the goal of repurposing cyclophilin inhibitors as broadly-acting antivirals.
Cell-intrinsic antiviral responses that target replication organelles to inhibit viral replication
There are more than 200 interferon-stimulated genes (ISGs) that encode proteins with antiviral activities. These proteins inhibit viral entry (e.g., IFITMs), viral replication (e.g., viperin) and release of new virions (e.g., tetherin). Cholesterol-25-hydroxylase is an ISG that blocks formation of the HCV replication organelle through production of the metabolite 25-hydroxycholesterol (Kusuma et al. (2015) Hepatology). We are extending these studies to other ISGs and other positive-sense RNA viruses, to understand the role of ISGs in antagonizing viral replication organelles. By learning from the innate immune system, we aim to identify and develop broad antiviral strategies to inhibit positive-sense RNA virus replication through disruption of the replication organelle.