Fig. 6: Proposed model of PMI-mediated glycolysis reprogramming and glycosylation to affect tissue tolerance and virus fitness.

Virus infection triggers heightened energetic demand including increased glucose influx and upregulated glycolysis. Mannose antagonizes such process by completing with glucose for glucose translocation across the cell membrane (GLUT), as well as for hexokinase enzyme (HK2) that are critically required during glycolysis. Consequently, this metabolic reprogramming by mannose normalizes the mitochondrial dysfunction as evidenced by heightened membrane potential and reactive oxygen species. It also reverses the abnormally high production of succinate from TCA cycle, HIF-1α activation and induction of overwhelming IL-1β that causing tissue damage. PMI is a gatekeeper that determines it is beneficial or unfavorable during glycolysis remodeling after mannose supplement. PMI can be also taken as a druggable target that affects a panel of virus entry. Mechanistically, PMI contributes to both host ACE2 and virus spike glycosylation thus controls SARS-CoV-2 entry. Created with BioRender.com.