Administration of L-citrulline prevents Plasmodium growth by inhibiting/ modulating T-regulatory cells during malaria pathogenesis

Background & objectives: Malaria affects around 228 million people all over the globe. Malaria causing parasite Plasmodium infection leads to activation of immune responses. The growth of parasite and immune activation requires semi essential amino acids like L-arginine. Malaria infection leads to condition of hyperargininemia and low availability of nitric oxide. However, the effect of L-arginine supplementation in malaria infected mice has not been explored in in-vivo studies. In this study we have compared the effect of oral supplementation of nitric oxide donor, L-arginine and L-citrulline, in malaria infected mice Methods: To examine the effect of oral supplementation of L-arginine and L-citrulline, Plasmodium berghei infected mice were divided in different groups and respective groups were fed with L- arginine and L-citrulline, parasitemia was measured on different days. Mice was sacrificed and immunophenotyping was done on 10 days post infection. Results: our results show that supplementation of L-arginine induces conducive environment for Plasmodium growth due to which the infected mice dies earlier than control wild type infected mice whereas L-citrulline supplementation inhibits parasite growth and mice survives for longer period of time. Flow cytometric analysis shows that supplementation of L-arginine increases cTLA-4 on T cell population, increases Treg cells leading to immunosuppression while supplementation of L-citrulline does not have effect on T cells population and number of Treg cell decrease compared to P. berghei infected mice. Interpretation & conclusion: our results show that L-citrulline can be a better alternative than L-arginine because of lower expression of inhibitory molecules and lower parasitemia as well as increased survival of infected mice.