Motran, C. C. | bioRxiv Science

bioRxiv2026

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.

immunology↗

bioRxiv2020

Wnt Signalling Orchestrates the Immune Response and Cardiac Damage During Trypanosoma cruzi Infection

Chagas cardiomyopathy is the consequence of a compromised electrical and mechanical cardiac function, with parasite persistence, unbalanced inflammation and pathological tissue remodelling, being intricately related to the myocardial aggression and the impaired function. Recent studies have shown that Wnt signalling pathways, which are important for developmental processes, play a critical role in the pathogenesis of cardiac and vascular diseases. In addition, we have reported that Trypanosoma cruzi infection activates Wnt signalling pathways in macrophages to promote their intracellular replication, with treatment of mice with IWP-L6 (an inhibitor of the O-acyl-transferase, PORCN, responsible for the post-translational modifications necessary for Wnt proteins secretion) being able to diminish parasitaemia and tissue parasitism. Therefore, Wnt signalling may contribute to the development of Chagas cardiomyopathy. In this work we have evaluated the effectiveness of Wnt secretion inhibition to control the parasite replication, modulate the adaptive immune response, and prevent the development of cardiac lesions in an experimental model of chronic Chagas disease. The IWP-L6 treatment, administered to T. cruzi infected BALB/c mice in a time window during the acute phase of the infection, was able to control the parasitaemia and heart parasitism together with the amelioration of the electrical, mechanical and histopathological cardiac alterations observed in chronically infected mice. Moreover, we demonstrated that during the acute phase of the infection Wnt signalling activation contributes to promote specific Th2-type immune response and to maintain the suppressive activity of Treg cells. Our data provide evidence that inhibition of Wnt signalling during the acute phase of T. cruzi infection controls the parasite replication, inhibits the development of parasite-prone and fibrosis-prone Th2-type immune response and prevents the development of cardiac lesions characteristics of chronic Chagas disease. Our study suggests that Wnt signalling pathway might be a potential target to prevent the development of T. cruzi-induced cardiomyopathy.

immunology↗