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1. Toxoplasma acyl-CoA synthetase TgACS3 is crucial to channel host fatty acids in lipid droplets and for parasite propagation

Author

Sheena Dass, Serena Shunmugam, Sarah Charital, Samuel Duley, Christophe-Sébastien Arnold, Nicholas J. Katris, Pierre Cavaillès, Marie-France Cesbron-Delauw, Yoshiki Yamaryo-Botté, and Cyrille Y. Botté

Subjects
Toxoplasma gondii, apicomplexa, host-parasite metabolic interactions, Lipid metabolism, membrane biogenesis, fatty acid activation, Biochemistry, QD415-436
Abstract

Apicomplexa comprise important pathogenic parasitic protists that heavily depend on lipid acquisition to survive within their human host cells. Lipid synthesis relies on the incorporation of an essential combination of fatty acids (FAs) either generated by a metabolically adaptable de novo synthesis in the parasite or by scavenging from the host cell. The incorporation of FAs into membrane lipids depends on their obligate metabolic activation by specific enzyme groups, acyl-CoA synthetases (ACSs). Each ACS has its own specificity, so it can fulfill specific metabolic functions. Whilst such functionalities have been well studied in other eukaryotic models, their roles and importance in Apicomplexa are currently very limited, especially for Toxoplasma gondii. Here, we report the identification of seven putative ACSs encoded by the genome of T. gondii (TgACS), which localize to different sub-cellular compartments of the parasite, suggesting exclusive functions. We show that the perinuclear/cytoplasmic TgACS3 regulates the replication and growth of Toxoplasma tachyzoites. Conditional disruption of TgACS3 shows that the enzyme is required for parasite propagation and survival, especially under high host nutrient content. Lipidomic analysis of parasites lacking TgACS3 reveals its role in the activation of host-derived FAs that are used for i) parasite membrane phospholipid and ii) storage triacylglycerol (TAG) syntheses, allowing proper membrane biogenesis of parasite progenies. Altogether, our results reveal the role of TgACS3 as the bulk FA activator for membrane biogenesis allowing intracellular division and survival in T. gondii tachyzoites, further pointing to the importance of ACS and FA metabolism for the parasite.

Published
2024
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2. The acyl-CoA synthetase TgACS1 allows neutral lipid metabolism and extracellular motility in Toxoplasma gondii through relocation via its peroxisomal targeting sequence (PTS) under low nutrient conditions

Author

Sarah Charital, Serena Shunmugam, Sheena Dass, Anna Maria Alazzi, Christophe-Sébastien Arnold, Nicholas J. Katris, Samuel Duley, Nyamekye A. Quansah, Fabien Pierrel, Jérôme Govin, Yoshiki Yamaryo-Botté, and Cyrille Y. Botté

Subjects
Toxoplasma gondii, lipid, fatty acid, acylCoA synthetase, lipidomics, fatty acid metabolism, Microbiology, QR1-502
Abstract

ABSTRACTApicomplexa parasites cause major diseases such as toxoplasmosis and malaria that have major health and economic burdens. These unicellular pathogens are obligate intracellular parasites that heavily depend on lipid metabolism for the survival within their hosts. Their lipid synthesis relies on an essential combination of fatty acids (FAs) obtained from both de novo synthesis and scavenging from the host. The constant flux of scavenged FA needs to be channeled toward parasite lipid storage, and these FA storages are timely mobilized during parasite division. In eukaryotes, the utilization of FA relies on their obligate metabolic activation mediated by acyl-co-enzyme A (CoA) synthases (ACSs), which catalyze the thioesterification of FA to a CoA. Besides the essential functions of FA for parasite survival, the presence and roles of ACS are yet to be determined in Apicomplexa. Here, we identified TgACS1 as a Toxoplasma gondii cytosolic ACS that is involved in FA mobilization in the parasite specifically during low host nutrient conditions, especially in extracellular stages where it adopts a different localization. Heterologous complementation of yeast ACS mutants confirmed TgACS1 as being an Acyl-CoA synthetase of the bubble gum family that is most likely involved in β-oxidation processes. We further demonstrate that TgACS1 is critical for gliding motility of extracellular parasite facing low nutrient conditions, by relocating to peroxisomal-like area.IMPORTANCEToxoplasma gondii, causing human toxoplasmosis, is an Apicomplexa parasite and model within this phylum that hosts major infectious agents, such as Plasmodium spp., responsible for malaria. The diseases caused by apicomplexans are responsible for major social and economic burdens affecting hundreds of millions of people, like toxoplasmosis chronically present in about one-third of the world’s population. Lack of efficient vaccines, rapid emergence of resistance to existing treatments, and toxic side effects of current treatments all argue for the urgent need to develop new therapeutic tools to combat these diseases. Understanding the key metabolic pathways sustaining host-intracellular parasite interactions is pivotal to develop new efficient ways to kill these parasites. Current consensus supports parasite lipid synthesis and trafficking as pertinent target for novel treatments. Many processes of this essential lipid metabolism in the parasite are not fully understood. The capacity for the parasites to sense and metabolically adapt to the host physiological conditions has only recently been unraveled. Our results clearly indicate the role of acyl-co-enzyme A (CoA) synthetases for the essential metabolic activation of fatty acid (FA) used to maintain parasite propagation and survival. The significance of our research is (i) the identification of seven of these enzymes that localize at different cellular areas in T. gondii parasites; (ii) using lipidomic approaches, we show that TgACS1 mobilizes FA under low host nutrient content; (iii) yeast complementation showed that acyl-CoA synthase 1 (ACS1) is an ACS that is likely involved in peroxisomal β-oxidation; (iv) the importance of the peroxisomal targeting sequence for correct localization of TgACS1 to a peroxisomal-like compartment in extracellular parasites; and lastly, (v) that TgACS1 has a crucial role in energy production and extracellular parasite motility.

Published
2024
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3. The structure of a Plasmodium vivax Tryptophan Rich Antigen domain suggests a lipid binding function for a pan-Plasmodium multi-gene family

Author

Prasun Kundu, Deboki Naskar, Shannon J. McKie, Sheena Dass, Usheer Kanjee, Viola Introini, Marcelo U. Ferreira, Pietro Cicuta, Manoj Duraisingh, Janet E. Deane, and Julian C. Rayner

Subjects
Science
Abstract

Abstract Tryptophan Rich Antigens (TRAgs) are encoded by a multi-gene family found in all Plasmodium species, but are significantly expanded in P. vivax and closely related parasites. We show that multiple P. vivax TRAgs are expressed on the merozoite surface and that one, PVP01_0000100 binds red blood cells with a strong preference for reticulocytes. Using X-ray crystallography, we solved the structure of the PVP01_0000100 C-terminal tryptophan rich domain, which defines the TRAg family, revealing a three-helical bundle that is conserved across Plasmodium and has structural homology with lipid-binding BAR domains involved in membrane remodelling. Biochemical assays confirm that the PVP01_0000100 C-terminal domain has lipid binding activity with preference for sulfatide, a glycosphingolipid present in the outer leaflet of plasma membranes. Deletion of the putative orthologue in P. knowlesi, PKNH_1300500, impacts invasion in reticulocytes, suggesting a role during this essential process. Together, this work defines an emerging molecular function for the Plasmodium TRAg family.

Published
2023
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4. Development of a Plasmodium vivax biobank for functional ex vivo assays

Author

Rashmi Dash, Kristen M. Skillman, Ligia Pereira, Anjali Mascarenhas, Sheena Dass, Jayashri Walke, Anvily Almeida, Mezia Fernandes, Edwin Gomes, John White, Laura Chery-Karschney, Anar Khandeparkar, Pradipsinh K. Rathod, Manoj T. Duraisingh, and Usheer Kanjee

Subjects
Plasmodium vivax, Cryopreservation, Short-term culture, Biobank, Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Plasmodium vivax is the second most prevalent cause of malaria yet remains challenging to study due to the lack of a continuous in vitro culture system, highlighting the need to establish a biobank of clinical isolates with multiple freezes per sample for use in functional assays. Different methods for cryopreserving parasite isolates were compared and subsequently the most promising one was validated. Enrichment of early- and late-stage parasites and parasite maturation were quantified to facilitate assay planning. Methods In order to compare cryopreservation protocols, nine clinical P. vivax isolates were frozen with four glycerolyte-based mixtures. Parasite recovery post thaw, post KCl-Percoll enrichment and in short-term in vitro culture was measured via slide microscopy. Enrichment of late-stage parasites by magnetic activated cell sorting (MACS) was measured. Short and long-term storage of parasites at either − 80 °C or liquid nitrogen were also compared. Results Of the four cryopreservation mixtures, one mixture (glycerolyte:serum:RBC at a 2.5:1.5:1 ratio) resulted in improved parasite recovery and statistically significant (P 20% trophozoites, schizonts and gametocytes) was observed in 60.0% of isolates by 48 h. Enrichment of mature parasite stages via MACS showed good reproducibility, with an average of 30.0% post-MACS parasitaemia and an average of 5.30 × 105 parasites/vial. Finally, the effect of storage temperature was tested, and no large impacts from short-term (7 days) or long-term (7–10 years) storage at − 80 °C on parasite recovery, enrichment or viability was observed. Conclusions Here, an optimized freezing method for P. vivax clinical isolates is demonstrated as a template for the generation and validation of a parasite biobank for use in functional assays.

Published
2023
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5. Toxoplasma LIPIN is essential in channeling host lipid fluxes through membrane biogenesis and lipid storage

Author

Sheena Dass, Serena Shunmugam, Laurence Berry, Christophe-Sebastien Arnold, Nicholas J. Katris, Samuel Duley, Fabien Pierrel, Marie-France Cesbron-Delauw, Yoshiki Yamaryo-Botté, and Cyrille Y. Botté

Subjects
Science
Abstract

Apicomplexa generate essential lipids as combination of host fatty acids and de novo synthesized within the apicoplast. Here, the authors identify a phosphatidic acid phosphatase in Toxoplasma gondii, TgLIPIN, as central for controlled lipid synthesis and define the host-scavenged lipidome.

Published
2021
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6. The flexibility of Apicomplexa parasites in lipid metabolism

Author

Serena Shunmugam, Christophe-Sébastien Arnold, Sheena Dass, Nicholas J. Katris, and Cyrille Y. Botté

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

Apicomplexa are obligate intracellular parasites responsible for major human infectious diseases such as toxoplasmosis and malaria, which pose social and economic burdens around the world. To survive and propagate, these parasites need to acquire a significant number of essential biomolecules from their hosts. Among these biomolecules, lipids are a key metabolite required for parasite membrane biogenesis, signaling events, and energy storage. Parasites can either scavenge lipids from their host or synthesize them de novo in a relict plastid, the apicoplast. During their complex life cycle (sexual/asexual/dormant), Apicomplexa infect a large variety of cells and their metabolic flexibility allows them to adapt to different host environments such as low/high fat content or low/high sugar levels. In this review, we discuss the role of lipids in Apicomplexa parasites and summarize recent findings on the metabolic mechanisms in host nutrient adaptation.

Published
2022

7. Division and Adaptation to Host Environment of Apicomplexan Parasites Depend on Apicoplast Lipid Metabolic Plasticity and Host Organelle Remodeling

Author

Souad Amiar, Nicholas J. Katris, Laurence Berry, Sheena Dass, Samuel Duley, Christophe-Sebastien Arnold, Melanie J. Shears, Camille Brunet, Bastien Touquet, Geoffrey I. McFadden, Yoshiki Yamaryo-Botté, and Cyrille Y. Botté

Subjects
Biology (General), QH301-705.5
Abstract

Summary: Apicomplexan parasites are unicellular eukaryotic pathogens that must obtain and combine lipids from both host cell scavenging and de novo synthesis to maintain parasite propagation and survival within their human host. Major questions on the role and regulation of each lipid source upon fluctuating host nutritional conditions remain unanswered. Characterization of an apicoplast acyltransferase, TgATS2, shows that the apicoplast provides (lyso)phosphatidic acid, required for the recruitment of a critical dynamin (TgDrpC) during parasite cytokinesis. Disruption of TgATS2 also leads parasites to shift metabolic lipid acquisition from de novo synthesis toward host scavenging. We show that both lipid scavenging and de novo synthesis pathways in wild-type parasites exhibit major metabolic and cellular plasticity upon sensing host lipid-deprived environments through concomitant (1) upregulation of de novo fatty acid synthesis capacities in the apicoplast and (2) parasite-driven host remodeling to generate multi-membrane-bound structures from host organelles that are imported toward the parasite. : Apicoplast de novo lipid synthesis and lipid host scavenging are both critical for apicomplexan intracellular development. Amiar et al. show that the parasite adapts to the fluctuations of host nutritional content to regulate the metabolic activity of both apicoplast and scavenging pathways and maintain parasite development and division. Keywords: Apicomplexa, toxoplasmosis, malaria, apicoplast, lipid synthesis, phosphatidic acid, host-parasite interaction, lipidomics, host nutritional environment, cytokinesis

Published
2020
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8. Toxoplasma gondii acetyl-CoA synthetase is involved in fatty acid elongation (of long fatty acid chains) during tachyzoite life stages

Author

David Dubois, Stella Fernandes, Souad Amiar, Sheena Dass, Nicholas J. Katris, Cyrille Y. Botté, and Yoshiki Yamaryo-Botté

Subjects
fatty acid synthesis and elongation, apicoplast, membrane biogenesis, lipidomics, stable isotope labeling, Biochemistry, QD415-436
Abstract

Apicomplexan parasites are pathogens responsible for major human diseases such as toxoplasmosis caused by Toxoplasma gondii and malaria caused by Plasmodium spp. Throughout their intracellular division cycle, the parasites require vast and specific amounts of lipids to divide and survive. This demand for lipids relies on a fine balance between de novo synthesized lipids and scavenged lipids from the host. Acetyl-CoA is a major and central precursor for many metabolic pathways, especially for lipid biosynthesis. T. gondii possesses a single cytosolic acetyl-CoA synthetase (TgACS). Its role in the parasite lipid synthesis is unclear. Here, we generated an inducible TgACS KO parasite line and confirmed the cytosolic localization of the protein. We conducted 13C-stable isotope labeling combined with mass spectrometry-based lipidomic analyses to unravel its putative role in the parasite lipid synthesis pathway. We show that its disruption has a minor effect on the global FA composition due to the metabolic changes induced to compensate for its loss. However, we could demonstrate that TgACS is involved in providing acetyl-CoA for the essential fatty elongation pathway to generate FAs used for membrane biogenesis. This work provides novel metabolic insight to decipher the complex lipid synthesis in T. gondii.

Published
2018
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9. Specific Targeting of Plant and Apicomplexa Parasite Tubulin through Differential Screening Using In Silico and Assay-Based Approaches

Author

Emmanuelle Soleilhac, Loraine Brillet-Guéguen, Véronique Roussel, Renaud Prudent, Bastien Touquet, Sheena Dass, Samia Aci-Sèche, Vinod Kasam, Caroline Barette, Anne Imberty, Vincent Breton, Marylin Vantard, Dragos Horvath, Cyrille Botté, Isabelle Tardieux, Sylvaine Roy, Eric Maréchal, and Laurence Lafanechère

Subjects
Tubulin, dinitroanilines, plant cells, Toxoplasma gondii, Plasmodium falciparum, virtual screening, small molecules, cell-based assays, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Dinitroanilines are chemical compounds with high selectivity for plant cell α-tubulin in which they promote microtubule depolymerization. They target α-tubulin regions that have diverged over evolution and show no effect on non-photosynthetic eukaryotes. Hence, they have been used as herbicides over decades. Interestingly, dinitroanilines proved active on microtubules of eukaryotes deriving from photosynthetic ancestors such as Toxoplasma gondii and Plasmodium falciparum, which are responsible for toxoplasmosis and malaria, respectively. By combining differential in silico screening of virtual chemical libraries on Arabidopsis thaliana and mammal tubulin structural models together with cell-based screening of chemical libraries, we have identified dinitroaniline related and non-related compounds. They inhibit plant, but not mammalian tubulin assembly in vitro, and accordingly arrest A. thaliana development. In addition, these compounds exhibit a moderate cytotoxic activity towards T. gondii and P. falciparum. These results highlight the potential of novel herbicidal scaffolds in the design of urgently needed anti-parasitic drugs.

Published
2018
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10. The structure of a Plasmodium vivax Tryptophan Rich Antigen suggests a lipid binding function for a pan-Plasmodium multi-gene family

Author

Prasun Kundu, Deboki Naskar, Shannon McKie, Sheena Dass, Usheer Kanjee, Viola Introini, Marcelo U. Ferreira, Manoj Duraisingh, Janet Deane, and Julian C. Rayner

Abstract

Tryptophan Rich Antigens (TRAgs) are encoded by a multi-gene family in all Plasmodium species, significantly expanded in P. vivax, but their function is not currently known. We show that multiple P. vivax TRAgs are expressed on the merozoite surface and that one, PVP01_0000100 binds red blood cells with a strong preference for reticulocytes. Solving the structure of the C-terminal tryptophan rich domain that defines the TRAg family revealed a three-helical bundle that is conserved across Plasmodium and has homology with lipid-binding BAR domains involved in membrane remodelling. Biochemical assays confirmed that this domain has lipid binding activity with preference for sulfatide, a glycosphingolipid present in the outer leaflet of plasma membranes. Deletion of the putative orthologue in P. knowlesi, PKNH_1300500, impacts invasion in reticulocytes, suggesting a role for membrane remodelling during this essential process. Together, this work suggests a molecular function for the TRAg family for the first time.

Published
2022

11. Division and Adaptation to Host Environment of Apicomplexan Parasites Depend on Apicoplast Lipid Metabolic Plasticity and Host Organelle Remodeling

Author

Melanie J. Shears, Souad Amiar, Samuel Duley, Laurence Berry, Sheena Dass, Yoshiki Yamaryo-Botté, Bastien Touquet, Nicholas J. Katris, Cyrille Y. Botté, Geoffrey I. McFadden, Camille Dorothée Brunet, Christophe-Sébastien Arnold, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)

Subjects
Male, 0301 basic medicine, Intracellular Space, Protozoan Proteins, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, Fatty Acids, Multivesicular Bodies, Adaptation, Physiological, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Cell biology, Toxoplasma, Cell Division, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Apicoplasts, Biology, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Host-Parasite Interactions, Apicomplexa, 03 medical and health sciences, Organelle, Animals, Humans, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Parasites, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cytokinesis, Dynamin, Life Cycle Stages, Apicoplast, Cell Membrane, Lipid metabolism, Nutrients, Lipid Metabolism, biology.organism_classification, De novo synthesis, 030104 developmental biology, lcsh:Biology (General), Lipidomics, Mutation, Fatty Acid Synthases, Acyltransferases, Gene Deletion, 030217 neurology & neurosurgery, Biogenesis
Abstract

Summary: Apicomplexan parasites are unicellular eukaryotic pathogens that must obtain and combine lipids from both host cell scavenging and de novo synthesis to maintain parasite propagation and survival within their human host. Major questions on the role and regulation of each lipid source upon fluctuating host nutritional conditions remain unanswered. Characterization of an apicoplast acyltransferase, TgATS2, shows that the apicoplast provides (lyso)phosphatidic acid, required for the recruitment of a critical dynamin (TgDrpC) during parasite cytokinesis. Disruption of TgATS2 also leads parasites to shift metabolic lipid acquisition from de novo synthesis toward host scavenging. We show that both lipid scavenging and de novo synthesis pathways in wild-type parasites exhibit major metabolic and cellular plasticity upon sensing host lipid-deprived environments through concomitant (1) upregulation of de novo fatty acid synthesis capacities in the apicoplast and (2) parasite-driven host remodeling to generate multi-membrane-bound structures from host organelles that are imported toward the parasite. : Apicoplast de novo lipid synthesis and lipid host scavenging are both critical for apicomplexan intracellular development. Amiar et al. show that the parasite adapts to the fluctuations of host nutritional content to regulate the metabolic activity of both apicoplast and scavenging pathways and maintain parasite development and division. Keywords: Apicomplexa, toxoplasmosis, malaria, apicoplast, lipid synthesis, phosphatidic acid, host-parasite interaction, lipidomics, host nutritional environment, cytokinesis

Published
2020

12. Basigin Interacts with Plasmodium vivax Tryptophan-rich Antigen PvTRAg38 as a Second Erythrocyte Receptor to Promote Parasite Growth

Author

Inderjeet Kaur, Sheena Dass, Sumit Rathore, Yagya D. Sharma, Mayank Gupta, and Divya Kandari

Subjects
0301 basic medicine, Erythrocytes, 030231 tropical medicine, Plasmodium vivax, Antigens, Protozoan, Plasma protein binding, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, Antigen, Anion Exchange Protein 1, Erythrocyte, Malaria, Vivax, Humans, Parasite hosting, Receptor, Molecular Biology, chemistry.chemical_classification, biology, Molecular Bases of Disease, Cell Biology, biology.organism_classification, Ligand (biochemistry), Amino acid, 030104 developmental biology, chemistry, Basigin, Peptides, Protein Binding
Abstract

Elucidating the molecular mechanisms of the host-parasite interaction during red cell invasion by Plasmodium is important for developing newer antimalarial therapeutics. Recently, we have characterized a Plasmodium vivax tryptophan-rich antigen PvTRAg38, which is expressed by its merozoites, binds to host erythrocytes, and interferes with parasite growth. Interaction of this parasite ligand with the host erythrocyte occurs through its two regions present at amino acid positions 167–178 (P2) and 197–208 (P4). Each region recognizes its own erythrocyte receptor. Previously, we identified band 3 as the chymotrypsin-sensitive erythrocyte receptor for the P4 region, but the other receptor, binding to P2 region, remained unknown. Here, we have identified basigin as the second erythrocyte receptor for PvTRAg38, which is resistant to chymotrypsin. The specificity of interaction between PvTRAg38 and basigin was confirmed by direct interaction where basigin was specifically recognized by P2 and not by the P4 region of this parasite ligand. Interaction between P2 and basigin is stabilized through multiple amino acid residues, but Gly-171 and Leu-175 of P2 were more critical. These two amino acids were also critical for parasite growth. Synthetic peptides P2 and P4 of PvTRAg38 interfered with the parasite growth independently but had an additive effect if combined together indicating involvement of both the receptors during red cell invasion. In conclusion, PvTRAg38 binds to two erythrocyte receptors basigin and band 3 through P2 and P4 regions, respectively, to facilitate parasite growth. This advancement in our knowledge on molecular mechanisms of host-parasite interaction can be exploited to develop therapeutics against P. vivax malaria.

Published
2017

13. Division and adaptation to host nutritional environment of apicomplexan parasites depend on apicoplast lipid metabolic plasticity and host organelles remodelling

Author

Sheena Dass, Cyrille Y. Botté, Melanie J. Shears, Souad Amiar, Geoffrey I. McFadden, Laurence Berry, Nicholas J. Katris, Yoshiki Yamaryo-Botté, Bastien Touquet, Camille Dorothée Brunet, and Mohamed-Ali Hakimi

Subjects
De novo synthesis, chemistry.chemical_compound, Apicoplast, chemistry, Host (biology), Acyltransferase, Organelle, Biology, Cytokinesis, Fatty acid synthesis, Cell biology, Dynamin
Abstract

Apicomplexan parasites are unicellular eukaryotes responsible for major human diseases including malaria and toxoplasmosis. Apicomplexan parasites must obtain and combine lipids both from host cell scavenging andde novosynthesis to maintain parasite propagation and survival within their human host. Major questions on the actual role for each lipid source or how these are regulated upon fluctuating host nutritional conditions remain unanswered. Characterization of an apicoplast acyltransferase TgATS2, shows that the apicoplast provides local (lyso)phosphatidic acid balance, which is required for the recruitment of a novel dynamin (TgDrpC) critical during parasite cytokinesis. Disruption of TgATS2 led parasites to shift metabolic lipid acquisition fromde novosynthesis towards host scavenging. Importantly, both lipid scavenging andde novosynthesis pathways exhibit major metabolic and cellular plasticity upon sensing host lipid-deprived environments through concomitant (i) up-regulation ofde novofatty acid synthesis capacities in the apicoplast, and (ii) parasite-driven host cell remodelling to generate multi-membrane-bound structures from host organelles that are imported towards the parasite.

Published
2019

14. Specific Targeting of Plant and Apicomplexa Parasite Tubulin through Differential Screening Using In Silico and Assay-Based Approaches

Author

Véronique Roussel, Bastien Touquet, Isabelle Tardieux, Emmanuelle Soleilhac, Caroline Barette, Dragos Horvath, Laurence Lafanechère, Eric Maréchal, Loraine Brillet-Guéguen, Renaud Prudent, Sylvaine Roy, Marylin Vantard, Cyrille Y. Botté, Vinod Kasam, Samia Aci-Sèche, Sheena Dass, Vincent Breton, Anne Imberty, Genetics and Chemogenomics (GenChem), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), ABiMS - Informatique et bioinformatique = Analysis and Bioinformatics for Marine Science (ABIMS), Fédération de recherche de Roscoff (FR2424), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physiologie cellulaire et végétale (LPCV), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Dynamique cellulaire et membranaire des interactions hôte-parasite (Equipe de recherche), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique de Clermont (LPC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromolécules Végétales (CERMAV ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Atip-Avenir and Finovi programs (CNRS-INSERM-Finovi Atip-Avenir Apicolipid projects), ANR-05-CIGC-0008,DOCK,Conformation Sampling and Docking on Girds(2005), ANR-12-PDOC-0028,ApicoLipid,ApicoLipid: Etude du rôle de l'apicoplaste dans la synthèse lipidique et la biogénèse des parasites Apicomplexa(2012), ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), ABiMS - Informatique et bioinformatique = Analysis and Bioinformatics for Marine Science (FR2424), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Mutations des activités, des espaces et des formes d'organisation dans les territoires ruraux (METAFORT), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF)-ENITA Clermont-AgroParisTech-Institut National de la Recherche Agronomique (INRA), Transduction du signal : signalisation calcium, phosphorylation et inflammation, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Corpusculaire - Clermont-Ferrand (LPC), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromolécules Végétales (CERMAV), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Université Grenoble Alpes (UGA)-Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), ANR-11-LABX-0024/11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), Imberty, Anne, Programme de recherche 'Calcul Intensif et Grilles de Calcul' - Conformation Sampling and Docking on Girds - - DOCK2005 - ANR-05-CIGC-0008 - CIGC - VALID, Retour Post-Doctorant - ApicoLipid: Etude du rôle de l'apicoplaste dans la synthèse lipidique et la biogénèse des parasites Apicomplexa - - ApicoLipid2012 - ANR-12-PDOC-0028 - PDOC - VALID, and Laboratoires d'excellence - Alliance française contre les maladies parasitaires - - ParaFrap2011 - ANR-11-LABX-0024 - LABX - VALID

Subjects
Models, Molecular, 0301 basic medicine, tubuline, cell-based assays, Protein Conformation, [SDV]Life Sciences [q-bio], Dinitroaniline, Microtubules, lcsh:Chemistry, chemistry.chemical_compound, Tubulin, [CHIM] Chemical Sciences, Arabidopsis thaliana, Photosynthesis, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, Spectroscopy, biology, cellule végétale, food and beverages, General Medicine, Plants, dinitroanilines, plant cells, Toxoplasma gondii, Plasmodium falciparum, virtual screening, small molecules, 3. Good health, Computer Science Applications, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Biochemistry, In silico, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Catalysis, Inorganic Chemistry, Apicomplexa, 03 medical and health sciences, Microtubule, parasitic diseases, Animals, Humans, [CHIM]Chemical Sciences, Physical and Theoretical Chemistry, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Biology, Virtual screening, fungi, Organic Chemistry, dinitroaniline, biology.organism_classification, 030104 developmental biology, chemistry, lcsh:Biology (General), lcsh:QD1-999, biology.protein, HeLa Cells
Abstract

Dinitroanilines are chemical compounds with high selectivity for plant cell &alpha, tubulin in which they promote microtubule depolymerization. They target &alpha, tubulin regions that have diverged over evolution and show no effect on non-photosynthetic eukaryotes. Hence, they have been used as herbicides over decades. Interestingly, dinitroanilines proved active on microtubules of eukaryotes deriving from photosynthetic ancestors such as Toxoplasma gondii and Plasmodium falciparum, which are responsible for toxoplasmosis and malaria, respectively. By combining differential in silico screening of virtual chemical libraries on Arabidopsis thaliana and mammal tubulin structural models together with cell-based screening of chemical libraries, we have identified dinitroaniline related and non-related compounds. They inhibit plant, but not mammalian tubulin assembly in vitro, and accordingly arrest A. thaliana development. In addition, these compounds exhibit a moderate cytotoxic activity towards T. gondii and P. falciparum. These results highlight the potential of novel herbicidal scaffolds in the design of urgently needed anti-parasitic drugs.

Published
2018

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