NAD + modulation by nicotinamide riboside enhances CD8 + T-cell metabolic fitness and effector function during Trypanosoma cruzi infection and improves parasite control

Chagas disease, caused by the parasite Trypanosoma cruzi , remains a major health concern, with effective immune control relying heavily on CD8 + T cells. However, the metabolic factors that regulate CD8 + T cell function during infection are not well understood. Acute T. cruzi infection induced metabolic remodeling in parasite-specific and effector CD8 + T cells, characterized by increased reliance on glycolysis, altered mitochondrial homeostasis, oxidative stress, and increased CD38 expression. Nicotinamide riboside (NR), an NAD + precursor, improved mitochondrial function, reduced mitochondrial reactive oxygen species (mROS) and CD38 expression, decreased apoptosis, and enhanced CD8 + T cell effector responses in vitro and in infected mice. In vivo , NR treatment increased intracellular NAD + levels in CD8 + T cells and improved parasite control during acute infection, reducing parasitemia and skeletal muscle parasite burden. Furthermore, transient NR supplementation was associated with persistent metabolic and functional changes in memory CD8 + T cells during chronic infection. These findings identify NAD + metabolism as a modulator of CD8 + T cell metabolic fitness during T. cruzi infection and support its further investigation as a host-directed strategy to enhance parasite control.