Reprogramming host d-mannose metabolism for reduced virus replication and elevated tolerance of inflammatory damage
Description
Host survival during acute viral infections depends on the elimination of pathogens and mitigation of tissue damage otherwise antivirals or immunomodulatory treatments are essential. One mechanism affecting tolerance is the intensity of an immune response. An overly exuberant immune response can cause collateral damage through immune effectors and because of the energy allocated away from other physiological functions. Herein, we report that the modulation of d-mannose flux, rewires the virus-triggered immunometabolic response cascade, thus ameliorating tissue damage. The beneficial role of d-mannose is achievable via competing with glucose for the same transporter GLUT and same hexokinase. Such alterations impair glucose metabolism by raising intracellular mannose-6-phosphate levels, and result in the suppression of succinate-mediated hypoxia-inducible factor-1α (HIF-1α) activation, imposing a consequent reduction of virus-induced proinflammatory cytokines production including interleukin-1β. As expected, combinatorial treatment of the mannose and FDA-approved antiviral monotherapy exhibits in vivo synergy, particularly in a delayed treatment setting. We found that phosphomannose isomerase (PMI) activity dictates the host response to mannose. Ectopic overexpression of PMI and/or supplement of downstream PMI metabolite fructose 6-phosphate diminish the protective role of mannose. We also found that PMI is a druggable target with broad-spectrum potential. Both genetic depletion and pharmacological inhibition of PMI suppress a panel of virus replication. Mechanistically, PMI inhibition affects viral surface protein glycosylation thus blocks virus entry. These results highlight a mannose-centered and dual therapeutic strategy for therapeutic cure of viral diseases, that is the PMI-glycosylation axis for pathogen clearance, and HIF1α-IL1β axis for inflammation control.