Leishmania exploits the macrophage m6A reader IGF2BP2 for glycolytic reprogramming and host cell survival

We uncover a novel, epitranscriptomic strategy evolved in Leishmania parasites to subvert macrophage function enabling long-term infection. This mechanism targets the macrophage m ⁶ A reader protein IGF2BP2, inducing a unique phenotype in Leishmania-infected macrophages (LIMs) integrating characteristics specifically associated with Leishmania infection with features of M1 and M2 polarization. LIMs undergo a metabolic shift from an early M2-like state relying on respiratory energy production to a late M1-like state characterized by aerobic glycolysis and lactate secretion. Unlike typical M1 macrophages, this glycolytic shift in LIMs is not associated with HIF1-α induction but relies on IGF2BP2-mediated mRNA stabilization of hexokinase 2, a key glycolytic enzyme. Knock down of IGF2BP2 expression reduces glycolytic capacity and interferes with LIMs viability, which is rescued by lactate addition. These results reveal the importance of metabolic reprogramming in chronic Leishmania infection and uncover a novel, m ⁶ A-dependent subversion mechanism that likely has broader implications for other macrophage-targeting pathogens.