Ceramide mediates growth inhibition of the Plasmodium falciparum parasite

Pankova-Kholmyansky, Irene; Dagan, Arie; Gold, Daniel; Zaslavsky, Zeev; Skutelsky, Ehud; Gátt, Shimon; Flescher, Eliezer

doi:10.1007/s000180300049

Cited by 43 publications

(47 citation statements)

References 59 publications

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“…3E). Cer can be synthesized from host SM by the parasite sphingomyelinase (49) and can induce Plasmodium growth inhibition (54). Thus, Cer needs to be maintained at low physiological levels, as observed in our analysis (Fig.…”

Section: Resultsmentioning

confidence: 61%

Atypical lipid composition in the purified relict plastid (apicoplast) of malaria parasites

Botté

Yamaryo‐Botté

Rupasinghe

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

125

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The human malaria parasite Plasmodium falciparum harbors a relict, nonphotosynthetic plastid of algal origin termed the apicoplast. Although considerable progress has been made in defining the metabolic functions of the apicoplast, information on the composition and biogenesis of the four delimiting membranes of this organelle is limited. Here, we report an efficient method for preparing highly purified apicoplasts from red blood cell parasite stages and the comprehensive lipidomic analysis of this organelle. Apicoplasts were prepared from transgenic parasites expressing an epitope-tagged triosephosphate transporter and immunopurified on magnetic beads. Gas and liquid chromatography MS analyses of isolated apicoplast lipids indicated significant differences compared with total parasite lipids. In particular, apicoplasts were highly enriched in phosphatidylinositol, consistent with a suggested role for phosphoinositides in targeting membrane vesicles to apicoplasts. Apicoplast phosphatidylinositol and other phospholipids were also enriched in saturated fatty acids, which could reflect limited acyl exchange with other membrane phospholipids and/or a requirement for specific physical properties. Lipids atypical for plastids (sphingomyelins, ceramides, and cholesterol) were detected in apicoplasts. The presence of cholesterol in apicoplast membranes was supported by filipin staining of isolated apicoplasts. Galactoglycerolipids, dominant in plant and algal plastids, were not detected in P. falciparum apicoplasts, suggesting that these glycolipids are a hallmark of photosynthetic plastids and were lost when these organisms assumed a parasitic lifestyle. Apicoplasts thus contain an atypical melange of lipids scavenged from the human host alongside lipids remodeled by the parasite cytoplasm, and stable isotope labeling shows some apicoplast lipids are generated de novo by the organelle itself.

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Section: Resultsmentioning

confidence: 61%

Atypical lipid composition in the purified relict plastid (apicoplast) of malaria parasites

Botté

Yamaryo‐Botté

Rupasinghe

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

125

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“…In a recent review article, Deponte and Becker have reported TUNEL activity in P. falciparum blood-stage schizonts treated with antimalaria drugs and H 2 O 2 (7). Other studies have failed to detect TUNEL-positive assay results in P. falciparum parasites treated in vitro with known antimalarial drugs (38,39). Taken together, the presence of "crisis forms" and TUNEL-positive parasites suggests that febrile temperature-induced parasite killing is mediated by the mechanism of apoptotic cell death.…”

Section: Resultsmentioning

confidence: 91%

Molecular Factors and Biochemical Pathways Induced by Febrile Temperature in Intraerythrocytic Plasmodium falciparum Parasites

et al. 2007

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Intermittent episodes of febrile illness are the most benign and recognized symptom of infection with malaria parasites, although the effects on parasite survival and virulence remain unclear. In this study, we identified the molecular factors altered in response to febrile temperature by measuring differential expression levels of individual genes using high-density oligonucleotide microarray technology and by performing biological assays in asexual-stage Plasmodium falciparum parasite cultures incubated at 37°C and 41°C (an elevated temperature that is equivalent to malaria-induced febrile illness in the host). Elevated temperature had a profound influence on expression of individual genes; 336 of approximately 5,300 genes (6.3% of the genome) had altered expression profiles. Of these, 163 genes (49%) were upregulated by twofold or greater, and 173 genes (51%) were downregulated by twofold or greater. In-depth sensitive sequence profile analysis revealed that febrile temperature-induced responses caused significant alterations in the major parasite biologic networks and pathways and that these changes are well coordinated and intricately linked. One of the most notable transcriptional changes occurs in genes encoding proteins containing the predicted Pexel motifs that are exported into the host cytoplasm or inserted into the host cell membrane and are likely to be associated with erythrocyte remodeling and parasite sequestration functions. Using our sensitive computational analysis, we were also able to assign biochemical or biologic functional predictions for at least 100 distinct genes previously annotated as "hypothetical." We find that cultivation of P. falciparum parasites at 41°C leads to parasite death in a time-dependent manner. The presence of the "crisis forms" and the terminal deoxynucleotidyltransferasemediated dUTP-biotin nick end labeling-positive parasites following heat treatment strongly support the notion that an apoptosis-like cell death mechanism might be induced in response to febrile temperatures. These studies enhance the possibility of designing vaccines and drugs on the basis of disruption in molecules and pathways of parasite survival and virulence activated in response to febrile temperatures.

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“…As a consequence, targeting SMase, SMS, and/or GCS could inhibit growth of the parasite (14,73). Conversely, excessive accumulation of ceramide may also be detrimental for the pathogen since treatment with exogenous ceramide inhibits parasitic growth through a nonapoptotic mechanism (71,109). Indeed, the antimalarial drugs artemisinin and mefloquine may exert their antiparasitic effects through the activation of SMase (109).…”

Section: Fig 2 Sphingolipid Biosynthetic Pathwaysmentioning

confidence: 99%

“…Conversely, excessive accumulation of ceramide may also be detrimental for the pathogen since treatment with exogenous ceramide inhibits parasitic growth through a nonapoptotic mechanism (71,109). Indeed, the antimalarial drugs artemisinin and mefloquine may exert their antiparasitic effects through the activation of SMase (109). The consequent increase of ceramide would decrease the level of glutathione, thereby preventing degradation of ferroprotoporfirin IX, which is toxic to plasmodia.…”

Section: Fig 2 Sphingolipid Biosynthetic Pathwaysmentioning

confidence: 99%