scholarly journals Analysis of sex-specific lipid metabolism in P. falciparum gametocytes points to importance of sphingomyelin for gametocytogenesis

2021 ◽  
Author(s):  
Melanie C. Ridgway ◽  
Daniela Cihalova ◽  
Simon H. J. Brown ◽  
Phuong Tran ◽  
Todd W. Mitchell ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Lipid Metabolism ◽  
Mosquito Vector ◽  
Cholesteryl Esters ◽  
Ester Synthesis ◽  
Specific Nature ◽  
Male And Female ◽  
Sphingomyelin Synthase ◽  
Chemical Inhibition ◽  
Specific Lipid

Male and female Plasmodium falciparum gametocytes are the parasite lifecycle stage responsible for transmission of malaria from the human host to mosquito vector. Not only are gametocytes able to survive in radically different host environments, but they are also precursors for male and female gametes that reproduce sexually soon after ingestion by the mosquito. Here we investigate the sex-specific lipid metabolism of gametocytes within their host red blood cell and poised for ingestion by the mosquito vector and subsequent sexual reproduction. Comparison of the male and female lipidome identifies cholesteryl esters and dihydrosphingomyelin enrichment in female gametocytes. Chemical inhibition of each of these lipid types in mature gametocytes suggests dihydrosphingomyelin synthesis but not cholesteryl ester synthesis is important for sex-specific gametocyte viability. Genetic disruption of each of the two sphingomyelin synthase gene points towards sphingomyelin synthesis contributing to gametocytogenesis. This study shows that gametocytes are not only distinct from asexual stages, but that the lipid composition is also vastly different between male and female gametocytes, reflecting the different cellular roles these stages play. Together our results highlight the sex-specific nature of gametocyte lipid metabolism that has the potential to be targeted to block malaria transmission.

scholarly journals Analysis of sex-specific lipid metabolism of P. falciparum points to importance of sphingomyelin for gametocytogenesis

2021 ◽  
Author(s):  
Melanie C. Ridgway ◽  
Daniela Cihalova ◽  
Simon H.J. Brown ◽  
Phuong Tran ◽  
Todd W. Mitchell ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Lipid Metabolism ◽  
Mosquito Vector ◽  
Cholesteryl Esters ◽  
Ester Synthesis ◽  
Specific Nature ◽  
Male And Female ◽  
Sphingomyelin Synthase ◽  
Chemical Inhibition ◽  
Specific Lipid

Male and female Plasmodium falciparum gametocytes are the parasite lifecycle stage responsible for transmission of malaria from the human host to mosquito vector. Not only are gametocytes able to survive in radically different host environments, but they are also precursors for male and female gametes that reproduce sexually soon after ingestion by the mosquito. Here we investigate the sex-specific lipid metabolism of gametocytes within their host red blood cell. Comparison of the male and female lipidome identifies cholesteryl esters and dihydrosphingomyelin enrichment in female gametocytes. Chemical inhibition of each of these lipid types in mature gametocytes suggests dihydrosphingomyelin synthesis but not cholesteryl ester synthesis is important for gametocyte viability. Genetic disruption of each of the two sphingomyelin synthase gene points towards sphingomyelin synthesis contributing to gametocytogenesis. This study shows that gametocytes are distinct from asexual stages, and that the lipid composition is also vastly different between male and female gametocytes, reflecting the different cellular roles these stages play. Together our results highlight the sex-specific nature of gametocyte lipid metabolism that has the potential to be targeted to block malaria transmission.

scholarly journals Supplemental L-arginine improves feed conversion and modulates lipid metabolism in male and female broilers from 29 to 42 days of age

animal ◽  
2020 ◽  
pp. 100120
Author(s):  
S.T.S. Filho ◽  
E.M. da C. Lima ◽  
D.H. de Oliveira ◽  
M.L.T. de Abreu ◽  
P.V. Rosa ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Feed Conversion ◽  
Male And Female

The modified mitochondrial outer membrane carrier MTCH2 links mitochondrial fusion to lipogenesis

2021 ◽  
Vol 220 (11) ◽  
Author(s):  
Katherine Labbé ◽  
Shona Mookerjee ◽  
Maxence Le Vasseur ◽  
Eddy Gibbs ◽  
Chad Lerner ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Carrier ◽  
Cellular Survival ◽  
Mitochondrial Elongation ◽  
Specific Lipid

Mitochondrial function is integrated with cellular status through the regulation of opposing mitochondrial fusion and division events. Here we uncover a link between mitochondrial dynamics and lipid metabolism by examining the cellular role of mitochondrial carrier homologue 2 (MTCH2). MTCH2 is a modified outer mitochondrial membrane carrier protein implicated in intrinsic cell death and in the in vivo regulation of fatty acid metabolism. Our data indicate that MTCH2 is a selective effector of starvation-induced mitochondrial hyperfusion, a cytoprotective response to nutrient deprivation. We find that MTCH2 stimulates mitochondrial fusion in a manner dependent on the bioactive lipogenesis intermediate lysophosphatidic acid. We propose that MTCH2 monitors flux through the lipogenesis pathway and transmits this information to the mitochondrial fusion machinery to promote mitochondrial elongation, enhanced energy production, and cellular survival under homeostatic and starvation conditions. These findings will help resolve the roles of MTCH2 and mitochondria in tissue-specific lipid metabolism in animals.

scholarly journals Novel Method for the Separation of Male and Female Gametocytes of the Malaria Parasite Plasmodium falciparum That Enables Biological and Drug Discovery

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Melanie C. Ridgway ◽  
Kwong Sum Shea ◽  
Daniela Cihalova ◽  
Alexander G. Maier
Keyword(s):  
Flow Cytometry ◽  
Plasmodium Falciparum ◽  
Malaria Transmission ◽  
Disease Transmission ◽  
Severe Form ◽  
Male And Female ◽  
Content Type ◽  
Single Sex ◽  
Parasite Plasmodium Falciparum ◽  
Female Bias

ABSTRACT We developed a flow-cytometry-based method to separate and collect cocultured male and female Plasmodium falciparum gametocytes responsible for malaria transmission. The purity of the collected cells was estimated at >97% using flow cytometry, and sorted cells were observed by Giemsa-stained thin-smear and live-cell fluorescence microscopy. The expression of validated sex-specific markers corroborated the sorting strategy. Collected male and female gametocytes were used to confirm three novel sex-specific markers by quantitative real-time PCR that were more enriched in sorted male and female gametocyte populations than existing sex-specific markers. We also applied the method as a proof-of-principle drug screen that allows the identification of drugs that kill gametocytes in a sex-specific manner. Since the developed method allowed for the separation of male and female parasites from the same culture, we observed for the first time a difference in development time between the sexes: females developed faster than males. Hence, the ability to separate male and female gametocytes opens the door to a new field of sex-specific P. falciparum gametocyte biology to further our understanding of malaria transmission. IMPORTANCE The protozoan Plasmodium falciparum causes the most severe form of human malaria. The development of sexual forms (so-called gametocytes) is crucial for disease transmission. However, knowledge of these forms is severely hampered by the paucity of sex-specific markers and the inability to extract single sex gametocytes in high purity. Moreover, the identification of compounds that specifically affect one sex is difficult due to the female bias of the gametocytes. We have developed a system that allows for the separation of male and female gametocytes from the same population. Applying our system, we show that male and female parasites mature at different rates, which might have implications for transmission. We also identified new sex-specific genes that can be used as sex markers or to unravel sex-specific functions. Our system will not only aid in the discovery of much needed gametocidal compounds, but it also represents a valuable tool for exploring malaria transmission biology.

scholarly journals A Novel Tool for the Generation of Conditional Knockouts To Study Gene Function across the Plasmodium falciparum Life Cycle

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Marta Tibúrcio ◽  
Annie S. P. Yang ◽  
Kazuhide Yahata ◽  
Pablo Suárez-Cortés ◽  
Hugo Belda ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Genetic Modification ◽  
Gene Deletion ◽  
Genetically Modify ◽  
Complex Life Cycle ◽  
Mosquito Vector ◽  
Parasite Line ◽  
Content Type ◽  
First Time

ABSTRACT Plasmodium falciparum has a complex life cycle that involves interaction with multiple tissues inside the human and mosquito hosts. Identification of essential genes at all different stages of the P. falciparum life cycle is urgently required for clinical development of tools for malaria control and eradication. However, the study of P. falciparum is limited by the inability to genetically modify the parasite throughout its life cycle with the currently available genetic tools. Here, we describe the detailed characterization of a new marker-free P. falciparum parasite line that expresses rapamycin-inducible Cre recombinase across the full life cycle. Using this parasite line, we were able to conditionally delete the essential invasion ligand AMA1 in three different developmental stages for the first time. We further confirm efficient gene deletion by targeting the nonessential kinase FIKK7.1. IMPORTANCE One of the major limitations in studying P. falciparum is that so far only asexual stages are amenable to rapid conditional genetic modification. The most promising drug targets and vaccine candidates, however, have been refractory to genetic modification because they are essential during the blood stage or for transmission in the mosquito vector. This leaves a major gap in our understanding of parasite proteins in most life cycle stages and hinders genetic validation of drug and vaccine targets. Here, we describe a method that supports conditional gene deletion across the P. falciparum life cycle for the first time. We demonstrate its potential by deleting essential and nonessential genes at different parasite stages, which opens up completely new avenues for the study of malaria and drug development. It may also allow the realization of novel vaccination strategies using attenuated parasites.

scholarly journals Revisiting gametocyte biology in malaria parasites

2019 ◽  
Vol 43 (4) ◽  
pp. 401-414 ◽  
Author(s):  
Priscilla Ngotho ◽  
Alexandra Blancke Soares ◽  
Franziska Hentzschel ◽  
Fiona Achcar ◽  
Lucia Bertuccini ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Blood Circulation ◽  
Malaria Parasite ◽  
Mosquito Vector ◽  
Human Malaria Parasite ◽  
Malaria Burden ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Low Levels ◽  
Transmission Biology

ABSTRACT Gametocytes are the only form of the malaria parasite that is transmissible to the mosquito vector. They are present at low levels in blood circulation and significant knowledge gaps exist in their biology. Recent reductions in the global malaria burden have brought the possibility of elimination and eradication, with renewed focus on malaria transmission biology as a basis for interventions. This review discusses recent insights into gametocyte biology in the major human malaria parasite, Plasmodium falciparum and related species.

scholarly journals Identification of MMV Malaria Box Inhibitors of Plasmodium falciparum Early-Stage Gametocytes Using a Luciferase-Based High-Throughput Assay

2013 ◽  
Vol 57 (12) ◽  
pp. 6050-6062 ◽  
Author(s):  
Leonardo Lucantoni ◽  
Sandra Duffy ◽  
Sophie H. Adjalley ◽  
David A. Fidock ◽  
Vicky M. Avery
Keyword(s):  
Plasmodium Falciparum ◽  
High Throughput ◽  
Early Stage ◽  
Blood Stage ◽  
Stage I ◽  
Mosquito Vector ◽  
Asexual Blood Stage ◽  
Content Type ◽  
Malaria Box ◽  
Gametocytocidal Activity

ABSTRACTThe design of new antimalarial combinations to treatPlasmodium falciparuminfections requires drugs that, in addition to resolving disease symptoms caused by asexual blood stage parasites, can also interrupt transmission to the mosquito vector. Gametocytes, which are essential for transmission, develop as sexual blood stage parasites in the human host over 8 to 12 days and are the most accessible developmental stage for transmission-blocking drugs. Considerable effort is currently being devoted to identifying compounds active against mature gametocytes. However, investigations on the drug sensitivity of developing gametocytes, as well as screening methods for identifying inhibitors of early gametocytogenesis, remain scarce. We have developed a luciferase-based high-throughput screening (HTS) assay using tightly synchronous stage I to III gametocytes from a recombinantP. falciparumline expressing green fluorescent protein (GFP)-luciferase. The assay has been used to evaluate the early-stage gametocytocidal activity of the MMV Malaria Box, a collection of 400 compounds with known antimalarial (asexual blood stage) activity. Screening this collection against early-stage (I to III) gametocytes yielded 64 gametocytocidal compounds with 50% inhibitory concentrations (IC50s) below 2.5 μM. This assay is reproducible and suitable for the screening of large compound libraries, with an average percent coefficient of variance (%CV) of ≤5%, an average signal-to-noise ratio (S:N) of >30, and a Z′ of ∼0.8. Our findings highlight the need for screening efforts directed specifically against early gametocytogenesis and indicate the importance of experimental verification of early-stage gametocytocidal activity in the development of new antimalarial candidates for combination therapy.

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