Malaria's metabolic misery...

Malaria parasites rely on host cell metabolism to survive - what if we could turn that dependency against them? The Molecular Parasitology Group (Kai Matuschewski) uncovered a critical role for sphingolipid metabolism, specifically acid sphingomyelinase (Asm), in supporting Plasmodium infection. They show that Asm activity increases in infected mice, raising ceramide levels in red blood cells. Blocking Asm with amitriptyline reduces parasitemia, protects against disease pathology, and preserves the blood-brain barrier in Plasmodium berghei infections. In vitro, amitriptyline impairs P. falciparum growth by disrupting glucose uptake and parasite development. These findings highlight a novel host-targeted approach to combat malaria by interfering with parasite-supportive lipid pathways. Check out their Biomedicine & Pharmacotherapy Article!

Abstract

Malaria remains a global health challenge, necessitating novel therapeutic approaches. Here, we explore the role of the sphingolipid metabolism in Plasmodium infection. We focus on the enzyme acid sphingomyelinase (Asm), which hydrolyzes sphingomyelin to ceramide, a structural but also bioactive membrane molecule. We demonstrate induction of Asm activity in infected mice, leading to elevated ceramide levels in infected red blood cells. Pharmacological inhibition of Asm with the functional inhibitor amitriptyline in Plasmodium yoelii (Py)- and Plasmodium berghei ANKA (PbA)-infected mice significantly reduces parasitemia and mitigates disease-associated pathology. Amitriptyline treatment also reduces T cell activation, preserving blood-brain barrier integrity upon PbA infection. Remarkably, we observe inhibition of Plasmodium falciparum growth in vitro upon exposure to amitriptyline. Mechanistically, we elucidate that amitriptyline impedes intra-erythrocytic parasite development, due to a reduced glucose uptake and thereby interfering with the spreading of blood-stage Plasmodium parasites. Our findings highlight the therapeutic promise of targeting sphingolipid metabolism to combat Plasmodium infections.