Reprogramming of host energy metabolism mediated by the TNF-iNOS-HIF-1α axis plays a key role in host resistance to Plasmodium infection

TNF has a dual effect in Plasmodium infection, bolstering the host’s immune defense while also triggering disease. Here, we show that TNF signaling hampers physical activity, food intake, and energy expenditure while enhancing glucose uptake by the liver and spleen as well as controlling parasitemia in P. chabaudi ( Pc )-infected mice. We also demonstrate that TNF is required for expression of inducible nitric oxide synthase (iNOS), stabilization of HIF-1α, expression of glucose transporter GLUT1 and enhanced glycolysis in monocytic cells from Pc -infected mice. Importantly, Pc - infected iNOS ^-/- , TNFR ^ΔLyz2 and HIF-1α ^ΔLyz2 mice show impaired release of TNF and glycolysis in monocytes, together with increased parasitemia and disease tolerance. Together, our findings reveal that TNF-iNOS-HIF-1α-induced glycolysis in monocytes plays a critical role in host defense and sickness behavior in Pc -infected mice.