title: Leishmania-induced biphasic ceramide generation in macrophages is crucial for uptake and survival of the parasite.
abstract: The initial macrophage-Leishmania donovani interaction results in the formation of membrane platforms, termed lipid rafts, that help in the entry of the parasite. Therefore, it is imperative that the parasite designs a strategy to modulate its uptake and survival within the macrophages. Herein, we report Leishmania-triggered biphasic ceramide generation. In the first phase, L. donovani promastigotes induce activation of acid sphingomyelinase (ASMase), which catalyzes the formation of ceramide from sphingomyelin. Inhibition of ASMase resulted in reduced uptake and infection with the parasite. In the second phase, de novo synthesis generates ceramide that reduces the cellular cholesterol level and displaces the cholesterol from the membrane, leading to enhanced membrane fluidity, disruption of rafts, and impaired antigen-presentation to the T cells. The results reveal a novel role for ceramide in the perspective of L. donovani infection and help formulate an antileishmanial strategy that can possibly be applied to other intracellular infections as well.
authors.affiliation: Division of Molecular Medicine, Bose Institute, India.
authors.forename: Saikat
authors.initials: S
authors.lastname: Majumder
authors.forename: Ranadhir
authors.initials: R
authors.lastname: Dey
authors.forename: Surajit
authors.initials: S
authors.lastname: Bhattacharjee
authors.forename: Abdur
authors.initials: A
authors.lastname: Rub
authors.forename: Gaurav
authors.initials: G
authors.lastname: Gupta
authors.forename: Suchandra
authors.initials: S
authors.lastname: Bhattacharyya Majumdar
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Saha
authors.forename: Subrata
authors.initials: S
authors.lastname: Majumdar
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D006790:Host-Parasite Interactions; D007893:Leishmania donovani / Q000276:immunology / Q000502:physiology*; D007898:Leishmaniasis, Visceral / Q000378:metabolism* / Q000469:parasitology; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism* / Q000469:parasitology; D008560:Membrane Fluidity; D021962:Membrane Microdomains / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism
chemical_list: D002518:Ceramides; D013107:Sphingolipids; D013109:Sphingomyelins; D002784:Cholesterol; D013108:Sphingomyelin Phosphodiesterase