The Wnt/β-catenin pathway is important for replication of SARS-CoV-2 and other pathogenic RNA viruses
Zaikun Xu, Mohamed Elaish, Cheung Pang Wong, Bardes B. Hassan, Joaquín López-Orozco, Alberto Felix-Lopez, Natacha S. Ogando, Les P. Nagata, Lara K. Mahal, Anil Kumar, Joyce A. Wilson, Ryan S. Noyce, Irv Mayers, Christopher Power, David H. Evans, Tom C. Hobman
Abstract
Understanding how viruses affect cellular pathways during infection may facilitate development of host cell-targeted therapeutics with broad-spectrum antiviral activity. The interferon (IFN) response is critical for reducing replication and pathogenesis of many viruses including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. Mounting evidence indicates that peroxisomes which are best known as metabolic organelles, function in the IFN response. Recently, we reported that the Wnt/β-catenin signaling pathway strongly suppresses peroxisome biogenesis. Here, we show that SARS-CoV-2 infection activates Wnt/β-catenin signaling and hypothesized that pharmacological inhibition of this pathway would result in increased peroxisome formation and enhanced IFN production. Indeed, Wnt/β-catenin signaling potently inhibits replication of SARS-CoV-2 and other pathogenic RNA viruses in vitro and reduces viral load, inflammation and clinical symptoms in a mouse model of COVID-19. As such, targeting this cellular pathway may have prophylactic and/or therapeutic value in reducing the disease burden caused by emerging viral pathogens.