Type â…  Interferon Activates PFKFB3-driven Glycolysis To Promote Bystander Anti-viral Effects In Macrophages

Innate immune system evolved to protect multicellular organisms from pathogens such as viruses. Pattern recognition of viral nucleic acids and the ensuing production of type Ⅰ interferons (IFN) are central to anti-viral innate immunity. However, it is currently unclear whether the latter events can engage a shift in the cells’metabolic programs as part of the overall anti-viral arsenal.Glucose metabolism lies in the center of cellular energy metabolism and is increasingly recognized to regulate multiple aspects of cell behaviors. The anaerobic portion of glucose breakdown, i.e. glycolysis, not only serves to rapidly produce ATP, but also to generate intermediate metabolites to be used as precursors for synthesis of various biomacromolecules. Therefore, glycolysis is often regulated according to different cellular needs.Hence, our study mainly focused on the connection and interaction between cellular glucose metabolism and antiviral innate immunity in different cell types. We identified a novel connection where virus-triggered type Ⅰ interferon up-regulates glycolytic flux selectively in macrophages, but not in mouse embryonic fibroblasts (MEFs). In a similar macrophage-specific manner, IFN treatment induced the expression of glycolytic activator phospho-fructose 2 kinase/fructose 2,6 biphosphatase 3 (PFKFB3), whose metabolic contributions were subsequently confirmed by gain- and loss-of function experiments. Interestingly, PFKFB3 heterozygous knockout macrophages exhibited a notable increase in viral susceptibility, whereas their MEF counterparts did not. The latter results suggest that although glycolysis may fuel biosynthetic processes and promote viral replication, a moderate change in PFKFB3 dosage does not directly affect virus-associated synthesis per se. Further analyses illustrate that PFKFB3-driven glycolysis promotes the bystander anti-viral activity in macrophages that appears to be largely attributed to their phagocytic activity. Indeed, IFN-induced glycolysis enhanced macrophage phagocytic rates, leading to enhanced engulfment of virus-infected cells. During phagocytosis, PFKFB3 is transiently recruited to the phagocytic cups near the newly formed actin filaments, presumably facilitating the use of glycolytic ATP for rapid actin polymerization, In addition, since PI3K activity is required for phagocysis and PFKFB3 dosage is positively associated with PI3K pathway activity in macrophages, a PI3K-dependent mechanism may also be involved.Overall, our results suggest a macrophage-specific metabolic regulation as a critical contributor to anti-viral immunity. This study lends us better understandings to the connections between cell metabolism and antiviral immunity and provided the potential molecular target for antiviral drugs.