Rhinovirus induces an anabolic reprogramming in host cell metabolism essential for viral replication

Abstract

Rhinoviruses (RVs) are responsible for the majority of upper airway infections; despite their high prevalence and the resulting economic burden, effective treatment is lacking. We report here that RV induces metabolic alterations in host cells, which offer an efficient target for antiviral intervention. We show that RV-infected cells rapidly up-regulate glucose uptake in a PI3K-dependent manner. In parallel, infected cells enhance the expression of the PI3K-regulated glucose transporter GLUT1. In-depth metabolomic analysis of RV-infected cells revealed a critical role of glucose mobilization from extracellular and intracellular pools via glycogenolysis for viral replication. Infection resulted in a highly anabolic state, including enhanced nucleotide synthesis and lipogenesis. Consistently, we observed that glucose deprivation from medium and via glycolysis inhibition by 2-deoxyglucose (2-DG) potently impairs viral replication. Metabolomic analysis showed that 2-DG specifically reverts the RV-induced anabolic reprogramming. In addition, treatment with 2-DG inhibited RV infection and inflammation in a murine model. Thus, we demonstrate that the specific metabolic fingerprint of RV infection can be used to identify new targets for therapeutic intervention.

Proteomics of SARS-CoV-2-infected host cells reveals therapy targets

“…glycolysis) inhibition on SARS-CoV-2 replication. 2-deoxy-D-glucose (2-DG), an inhibitor of hexokinase, the rate limiting enzyme in glycolysis, had previously been shown to be effective against other viruses in cell culture and suppressed rhinovirus infection in mice 18 . Blocking glycolysis with non-toxic concentrations of 2-DG prevented SARS-CoV-2 replication in Caco-2 cells (2-DG, Fig.…”

Metabolic changes during respiratory syncytial virus infection of epithelial cells

“…Therefore, it seems that HRSV, on the one hand, relies on the Warburg effect to promote the synthesis of the building blocks (nucleotides, amino acids, and lipids) for the virus structural components, and, on the other hand, on an anaplerotic reaction in which glutamine substitutes glucose as the predominant extracellular carbon source to feed the TCA cycle and generate energy. Rhinovirus infection also induces enhanced glucose uptake and increased levels of multiple nucleotides, indicating that this virus establishes an anabolic state in infected cells, in some aspects similar to HRSV [50]. Likewise, herpes simplex virus-1 (HSV-1) relies on glutamine uptake to feed the TCA cycle, while glucose is used to drive nucleotide synthesis [51].…”

Small‐Molecule Inhibition of Glucose Transporters GLUT‐1–4

“…Treatment with glycolysis inhibitor 2DG reverts the metabolism to lipogenesis. Thus GLUT inhibitors might open an alternative opportunity to address viral infection …”

“…Thus GLUT inhibitors might open an alternative opportunity to address viral infection. [54] Furthermore,t he transformation of progenitor cells to differentiatedc ells often involves as witch in the metabolic phenotype of the cell (Figure 3). Izumi et al recently demonstrated that the treatment of connective tissue with 2DG drives the differentiation to tendon cells and inhibits chondrogenesis, which is associated with poor tendon healing.…”