Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis

Abstract

BackgroundThe disturbance of host metabolic pathways by Leishmania parasites has crucial consequences for the activation status of immune cells and the outcome of infection. Glutamine has been described as an immunomodulatory amino acid, yet its role during Leishmania infection is still unknown.Visceral leishmaniasis is a life threatening neglected tropical disease affecting around 500,000 and killing 50,000 individuals a year. Despite its obligatory dependence on host cell metabolism and the lack of effective, non-toxic, orally bioavailable anti-leishmanial drugs, Leishmania-perturbed host cell metabolomes and its relation to anti-leishmanial chemotherapy remains unexplored. Transcriptomic analysis performed on L. donovaniinfected macrophages identified patterns of gene expression associated with glutamine metabolism. In vitro and in vivo pharmacological inhibition of glutaminase (GLS), which catalyzes the first reaction in the primary pathway for the catabolism of glutamine, significantly increased the susceptibility to infection demonstrating the role of glutamine metabolism to L. donovani infection. More importantly, we demonstrated that glutamine supplementation during miltefosine treatment potentiates L. donovani clearance through the development of a more effective anti-Leishmania innate and adaptive immune response. Overall, our work demonstrated that glutamine-miltefosine synergy is a novel combined host-and pathogen-directed treatment for combating visceral leishmaniasis.

Dysregulation of Glycerophosphocholines in the Cutaneous Lesion Caused by Leishmania major in Experimental Murine Models

“…These findings contrast with the metabolomic profiling of L. amazonensis -infected macrophages, which showed increased glutamine levels [ 22 ]. A recent study in mice infected with L. donovani, however, showed heightened glutamine consumption with infection and a role of glutamine supplementation in clearing parasite load [ 37 ], which concur with our findings. Future studies should aim to look at the specific functional role of the glutamine metabolism in L. major infection.…”

Glutamine reliance in cell metabolism

“…During cellular stress, such as nutrient starvation and catabolic stress after trauma, surgery, infection, sepsis, or cancer cachexia, blood glutamine levels are severely decreased 144 . Under these conditions, several studies have reported that glutamine supplementation can offer a therapeutic approach for these critical illnesses [145][146][147] . Glutamine has been considered an immunomodulatory amino acid in several disease states, yet the mechanisms underlying the therapeutic effects of glutamine supplementation in critical illness remain poorly understood.…”

Deletion of Glutamine Synthetase Gene Disrupts the Survivability and Infectivity of Leishmania donovani

“…Glutamine has been known to modulate immune response and play essential role for the control of L. donovani infection to macrophages. The gene of glutamine metabolism have been found to be upregulated in macrophages infected by L. donovani , as revealed by transcriptomic analysis ( Ferreira et al., 2020 ). It is known that the protein expression is more when the gene integration happens in the genome, as compared to episomal addition.…”