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 inducing sickness behavior. Here, we confirm 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 Plasmodium chabaudi (Pc)-infected mice. We also report that TNF is required for expression of inducible nitric oxide synthase (iNOS), stabilization of hypoxia-inducible factor 1α (HIF-1α), expression of glucose transporter GLUT1, and enhanced glycolysis in monocytic cells from Pc-infected mice. Importantly, Pc-infected Nos2-/-, TNFR1 cKO, and HIF-1a cKO mice show impaired release of TNF and glycolysis in monocytes, along with increased parasitemia and disease tolerance. Altogether, our results indicate that TNF-iNOS-HIF-1α-induced glycolysis in monocytes plays a critical role in host defense and sickness behavior in Pc-infected mice.