One drug to rule them all: Targeting host cell metabolic pathway to combat respiratory infections

Abstract

Human rhinoviruses (HRVs) and coronaviruses (HCoVs) are the primary cause of the ‚common cold‘, an upper respiratory tract infection, which is largely self-limiting in healthy individuals. On the other hand, HRV and HCoV infections are a major cause of exacerbations in patients with asthma or chronic obstructive pulmonary disease (COPD). The dependency of these viruses on host glucose metabolism for replication opens new avenues for the development of host cell-based antivirals. 2-Deoxyglucose (2-DG), an analogue of glucose, is phosphorylated to 2-DG6P in the cell. 2-DG6P leads to the arrest of glycolysis, thereby critically affecting viral replication. In this study, we characterized the intracellular kinetics of 2-DG6P and investigated the antiviral activity of 2-DG against various strains of HRV in HeLa Ohio cells and human nasal epithelial cells (HNEC). We could show that a brief exposure to 2-DG resulted in an extended intracellularly storage of the active form 2-DG6P. Treatment of HRV infected HeLa Ohio cells and HNECs with 2-DG led to a strong reduction in intracellular viral RNA as well as the amount of released virus. When we investigated the effectiveness of 2-DG in a prophylactic and therapeutic setting, the application of 2-DG prior, at the start and even hours after the viral infection showed a reduction in intracellular viral load. Concomitantly, we assessed 2-DG’s antiviral activity against endemic and pandemic HCoV. 2-DG treatment of HCoV infected cells showed a dose-dependent decrease in the amount of released virus. This study emphasizes that targeting the host cell metabolism holds great potential in combating viral infections.