PMI-controlled mannose metabolism and glycosylation determines tissue tolerance and virus fitness

This study explored the regulatory effect of D-mannose on host immunometabolic responses after viral infection. The results showed that D-mannose can compete with glucose for transporters and hexokinase, inhibiting glycolysis, reducing mitochondrial reactive oxygen species and succinate-induced HIF-1a, thereby reducing virus-induced inflammatory cytokine production. Even with delayed combinatorial treatment of D-mannose and antiviral monotherapy after viral infection, a synergistic effect was still observed in mouse models. Phosphomannose isomerase (PMI) activity determines the benefits of D-mannose, as simultaneous PMI depletion and mannose supplementation impaired cell viability. PMI inhibition can suppress replication of various viruses by affecting host and viral surface protein glycosylation. However, D-mannose does not inhibit PMI activity or viral fitness. In summary, PMI-centered therapeutic strategies can eliminate viral infections, while D-mannose treatment reprograms glycolysis to control collateral damage. Overall design: This study used a mouse model, divided into control group (Mock Infection), virus infection group (H1N1), and D-mannose treatment after viral infection group (H1N1-Mannose), with 3 mice per group. Metabolic changes, inflammatory factor expression, viral load and other indicators were measured at different time points after viral infection or treatment. By comparing the control group and the viral infection group, the impact of viral infection on mouse immune metabolism was evaluated. By comparing the viral infection group and the treatment group, the regulatory effect of D-mannose treatment on metabolism and inflammation was assessed.