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

Abstract 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. Importance CD8⁺ T cells are essential for controlling Trypanosoma cruzi , the intracellular parasite that causes Chagas disease, yet the contribution of cellular metabolism to their protective function remains poorly understood. Using a murine model of T. cruzi infection, this study shows that metabolic and mitochondrial alterations accompany the CD8⁺ T cell response and that nicotinamide riboside supplementation enhances CD8⁺ T cell metabolic fitness and function while increasing intracellular NAD + levels. These changes were associated with improved parasite control. Together, our findings highlight the metabolic state of CD8⁺ T cells as an important component of the immune response to T. cruzi and broaden our understanding of how host immunometabolism relates to the control of intracellular infection.