Metabolic Dysregulation in Acute SARS-CoV-2 Infection

Abstract

The global pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), mostly presented with mild to moderate or no symptoms and patients having pre-existing metabolic disorders like diabetes, cardiovascular diseases, and obesity are at risk for severe and critical cases of infection. The metabolic landscape of COVID-19 and its association with disease severity has urged the need to understand how metabolic reprogramming occurs during the acute SARS-CoV-2 infection with the ultimate goal toward therapeutic intervention. Viral replication is dependent on extracellular carbon sources such as glucose and glutamine and induces metabolic alterations in host cell including host central carbon metabolism, nucleotide, fatty acids, and lipid synthesis that modulate viral pathogenesis and host response. SARSCoV-2 dysregulation of PI3K/Akt/mTOR and hypoxia-inducible factor 1 (HIF-1) signaling pathways in infected cells and affect mitochondrial functions. These pathways regulate glycolysis by altering glucose transporters (GLUTs) across cell membranes. The altered extracellular glucose, mannose, and glutamate levels could be due to dysregulated carbohydrate metabolism and mitochondrial function. Host cellular response following SARSCoV-2 infection identified a strong acute metabolic adaptation in the lung epithelial cells (Calu-3) by modulating central carbon metabolism and indicative of mitochondrial dysfunction that is also observed in severe COVID-19 patients. Glycolysis and glutaminolysis can be essential for virus replication, and hostbased metabolic strategies to inhibit viruses to weaken the viral replication by metabolic intervention could be an attractive antiviral therapy. Targeting these pathways with inhibitors such as MK2206 (Akt inhibitor) or 2-deoxy-D-glucose (2-DG; glycolysis inhibitor) can lower the viral burden in the cells in vitro.