Highlights d HIF-1a is a protective factor against Leishmania donovani infection d In absence of HIF-1a, lipogenesis is induced via BNIP3/ mTOR/SREBP-1c modulation d Blockage of lipogenesis reverts HIF-1a-associated Leishmania susceptibility d HIF1A polymorphism correlates with susceptibility to infection

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.

Male infertility has been increasing over the last decades being nowadays a pressing health problem. Diabetes mellitus (DM) can contribute directly or indirectly to male infertility due to an abnormal spermatogenesis, which results in a decreased sperm quality. Type 2 Diabetes mellitus (T2DM) is responsible for the vast majority of DM cases, being frequently treated with oral antidiabetic drugs. Metformin is the most cost-effective therapy for the treatment of T2DM. This biguanide is an oral insulin-sensitizing agent capable of increasing insulin sensitivity and decreasing plasma fasting insulin levels. The main metabolic action of this drug occurs in the liver. However, it has been shown that metformin acts on a variety of organs including the male reproductive system. With the rising numbers of diabetic individuals among younger populations, there is an increase in the consumption of metformin in individuals of this age group. As a result, it is important to discuss the role of metformin in male fertility. This review presents the most recent data available from studies on the effects of metformin on male reproductive system. Together with the discussion of these effects, their significance to male fertility is also debated.

Visceral leishmaniasis (VL) is a fatal parasitic disease if untreated. Treatment options of VL diminish due to emerging drug resistance. Although the principal host cells for the multiplication of Leishmania are macrophages, neutrophils are the first cells infected with the parasites rapidly after parasite inoculation. Leishmania can survive in neutrophils despite the potent antimicrobial effector functions of neutrophils that can eliminate the parasites. Recently, the growing field of immunometabolism provided strong evidence for the therapeutic potential in targeting metabolic processes as a means of controlling immune effector functions. Therefore, the understanding of the immunometabolic profile of neutrophils during Leishmania infection could provide new promising targets for host-directed therapies against VL. To our knowledge, this is the first study addressing the bioenergetics profile of L. donovani-infected primary human neutrophils. Transcriptome analysis of L. donovani-infected neutrophils revealed an early significant upregulation of several glycolytic enzymes. Extracellular flux analysis showed that glycolysis and glycolytic capacity were upregulated in L. donovani-infected neutrophils at 6 h post infection. An increased glucose uptake and accumulation of glycolytic end products were further signs for an elevated glycolytic metabolism in L. donovani-infected neutrophils. At the same time point, oxidative phosphorylation provided NADPH for the oxidative burst but did not contribute to ATP production. Inhibition of glycolysis with 2-DG significantly reduced the survival of L. donovani promastigotes in neutrophils and in culture. However, this reduction was due to a direct antileishmanial effect of 2-DG and not a consequence of enhanced antileishmanial activity of neutrophils. To further address the impact of glucose metabolism during the first days of infection in vivo, we treated C57BL/6 mice with 2-DG prior to infection with L. donovani and assessed the parasite load one day and seven days post infection. Our results show, that seven days post-infection the parasite load of 2-DG treated animals was significantly higher than in mock treated animals. This data indicates that glycolysis serves as major energy source for antimicrobial effector functions against L. donovani. Inhibition of glycolysis abrogates important neutrophil effector functions that are necessary the initial control of Leishmania infection.

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