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1. Role of human group IIA secreted phospholipase A2 in malaria pathophysiology: Insights from a transgenic mouse model

Author

Christine Payré, Lhousseine Touqui, Gérard Lambeau, Amandine Labat, Christiane Deregnaucourt, Isabelle Lagrange, Mélanie Dacheux, Philippe Grellier, Alonso Joy, Franck Bihl, Soraya Chaouch, Agnès Petit-Paitel, Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), École nationale vétérinaire - Alfort (ENVA), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Mucoviscidose et bronchopathies chroniques : biopathologie et phénotype cliniques - Cystic Fibrosis and Bronchial Diseases, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported by the Museum National d’Histoire Naturelle (ATM blanche 2016-2017-2018 to C.D.) and by grants from Centre National de la Recherche Scientifique (CNRS), the Fondation du Rein (Award FdR 2018/FRM_G. Lambeau) and the Fondation Jean Valade/Fondation de France (Award FJV_FDF-00112090) to G.L., Gestionnaire, Hal Sorbonne Université, Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), École nationale vétérinaire d'Alfort (ENVA), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]

Subjects
0301 basic medicine, Genetically modified mouse, medicine.medical_specialty, Transgene, [SDV]Life Sciences [q-bio], Mice, Transgenic, Spleen, Group II Phospholipases A2, Biochemistry, Plasmodium chabaudi, Mice, 03 medical and health sciences, Th2 Cells, Phospholipase A2, In vivo, Internal medicine, parasitic diseases, medicine, Animals, Humans, Innate immune system, 030102 biochemistry & molecular biology, biology, Chemistry, General Medicine, Th1 Cells, biology.organism_classification, In vitro, Malaria, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Endocrinology, biology.protein, Cytokines
Abstract

International audience; We previously showed that injection of recombinant human group IIA secreted phospholipase A2 (hGIIA sPLA2) to Plasmodium chabaudi-infected mice lowers parasitaemia by 20%. Here, we show that transgenic (TG) mice overexpressing hGIIA sPLA2 have a peak of parasitaemia about 30% lower than WT littermates. During infection, levels of circulating sPLA2, enzymatic activity and plasma lipid peroxidation were maximal at day-14, the peak of parasitaemia. Levels of hGIIA mRNA increased in liver but not in spleen and blood cells, suggesting that liver may contribute as a source of circulating hGIIA sPLA2. Before infection, baseline levels of leukocytes and pro-inflammatory cytokines were higher in TG mice than WT littermates. Upon infection, the number of neutrophils, lymphocytes and monocytes increased and were maximal at the peak of parasitaemia in both WT and TG mice, but were higher in TG mice. Similarly, levels of the Th1 cytokines IFN-γ and IL-2 increased in WT and TG mice, but were 7.7- and 1.7-fold higher in TG mice. The characteristic shift towards Th2 cytokines was observed during infection in both WT and TG mice, with increased levels of IL-10 and IL-4 at day-14. The current data are in accordance with our previous in vitro findings showing that hGIIA kills parasites by releasing toxic lipids from oxidized lipoproteins. They further show that hGIIA sPLA2 is induced during mouse experimental malaria and has a protective in vivo role, lowering parasitaemia by likely releasing toxic lipids from oxidized lipoproteins but also indirectly by promoting a more sustained innate immune response.

Published
2021
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2. Antimalarial Activity of Human Group IIA Secreted Phospholipase A2 in Relation to Enzymatic Hydrolysis of Oxidized Lipoproteins

Author

Véronique Sinou, Christiane Deregnaucourt, Gérard Lambeau, Louise Jeammet, Christine Payré, Mélanie Dacheux, Daniel Parzy, Philippe Grellier, Columbia University College of Physicians and Surgeons, Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE17-0012,MNaims,Dissection moléculaire de la glomérulonéphrite extramembraneuse liée à PLA2R1: vers l'identification de nouveaux biomarqueurs cliniques(2017), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)

Subjects
0301 basic medicine, Immunology, Parasitemia, Microbiology, 03 medical and health sciences, 0302 clinical medicine, Phospholipase A2, parasitic diseases, Blood plasma, medicine, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, biology, Plasmodium falciparum, medicine.disease, biology.organism_classification, Blood proteins, 3. Good health, 030104 developmental biology, Infectious Diseases, Enzyme, chemistry, Blood chemistry, Biochemistry, biology.protein, Parasitology, 030217 neurology & neurosurgery, Lipoprotein
Abstract

The level of human group IIA secreted phospholipase A2 (hGIIA sPLA2) is increased in the plasma of malaria patients, but its role is unknown. In parasite culture with normal plasma, hGIIA is inactive against Plasmodium falciparum, contrasting with hGIIF, hGV, and hGX sPLA2s, which readily hydrolyze plasma lipoproteins, release nonesterified fatty acids (NEFAs), and inhibit parasite growth. Here, we revisited the anti-Plasmodium activity of hGIIA under conditions closer to those of malaria physiopathology where lipoproteins are oxidized. In parasite culture containing oxidized lipoproteins, hGIIA sPLA2 was inhibitory, with a 50% inhibitory concentration value of 150.0 ± 40.8 nM, in accordance with its capacity to release NEFAs from oxidized particles. With oxidized lipoproteins, hGIIF, hGV, and hGX sPLA2s were also more potent, by 4.6-, 2.1-, and 1.9-fold, respectively. Using specific immunoassays, we found that hGIIA sPLA2 is increased in plasma from 41 patients with malaria over levels for healthy donors (median [interquartile range], 1.6 [0.7 to 3.4] nM versus 0.0 [0.0 to 0.1] nM, respectively; P < 0.0001). Other sPLA2s were not detected. Malaria plasma, but not normal plasma, contains oxidized lipoproteins and was inhibitory to P. falciparum when spiked with hGIIA sPLA2 Injection of recombinant hGIIA into mice infected with P. chabaudi reduced the peak of parasitemia, and this was effective only when the level of plasma peroxidation was increased during infection. In conclusion, we propose that malaria-induced oxidation of lipoproteins converts these into a preferential substrate for hGIIA sPLA2, promoting its parasite-killing effect. This mechanism may contribute to host defense against P. falciparum in malaria where high levels of hGIIA are observed.

Published
2019
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3. Synthesis of an organo-ruthenium aminoquinoline-trioxane hybrid and evaluation of its activity against Plasmodium falciparum and its toxicity toward normal mammalian cells

Author

Alberto Martínez, Christiane Deregnaucourt, Joseph Schrevel, Véronique Sinou, Christine Latour, Roberto A. Sánchez-Delgado, Dipankar Roy, Molécules de Communication et Adaptation des Micro-Organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Chemistry Department of Brooklyn College and Ph.D. Program in Chemistry, CUNY Graduate Center (The Graduate Center), City University of New York [New York] (CUNY)-City University of New York [New York] (CUNY), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Chemistry Department, City University of New York [New York] (CUNY)-Brooklyn College [CUNY], City University of New York [New York] (CUNY)-The Graduate Center, and Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Ketone, Trioxane, chemistry.chemical_element, 01 natural sciences, Aminoquinoline, 03 medical and health sciences, chemistry.chemical_compound, Ruthenocene, medicine, Moiety, [CHIM]Chemical Sciences, General Pharmacology, Toxicology and Pharmaceutics, Artemisinin, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, biology, 010405 organic chemistry, Organic Chemistry, Plasmodium falciparum, biology.organism_classification, Combinatorial chemistry, 3. Good health, 0104 chemical sciences, Ruthenium, 030104 developmental biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, medicine.drug
Abstract

A new hybrid compound 5 containing a ruthenocene, a 4-aminoquinoline, and a 1,2,4-trioxane within a single molecular structure has been synthesized and evaluated for antimalarial potential. In order to ascertain the role of each component of hybrid 5, its antimalarial activity has been measured against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum in comparison with those of chloroquine, artemisinin, a ruthenocene-trioxane compound 9 not containing an aminoquinoline, the precursor trioxane ketone 4, and a trioxane dimer 10. Hybrid 5 displays high antimalarial activity, in the mid to low nanomolar IC50 range, and low cytotoxicity toward healthy mammalian cells, which translates into good selectivity indexes. The potency of 5 is consistently higher than those of chloroquine, the parent metal-free trioxane, and compound 9, the structural intermediate featuring a ruthenocene moiety bound to the trioxane but lacking the aminoquinoline. These results validate our hypothesis that it is the combination of the aminoquinoline, the ruthenocenyl moiety, and the trioxane in a single molecule that provides the enhanced antiplasmodial activity, and highlight the concept of hybrid compounds as a strategy that deserves further attention.

Published
2017
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4. Neurotoxicity and other pharmacological activities of the snake venom phospholipase A2 OS2: the N-terminal region is more important than enzymatic activity

Author

Gérard Lambeau, James G. Bollinger, Michel Lazdunski, Stéphane Canaan, José María Gutiérrez, Lachlan D. Rash, Michael H. Gelb, Christiane Deregnaucourt, Morgane Rouault, Joseph Schrével, Alain Doglio, Eric Boilard, Carole Guillaume, Thomas Maurin, Pierre Escoubas, Bruno Lomonte, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Departements of Chemistry and Biochemistry, Seattle University [Seattle], Faculdad de Microbiologia, Instituto Clodomiro Picado, Universidad Nacional de Costa Rica, Génétique et signalisation moléculaire (GSM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Molécules de Communication et Adaptation des Micro-Organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Enzymologie Interfaciale et de Physiologie de la Lipolyse - UPR9025 (EIPL), Université de la Méditerranée - Aix-Marseille 2-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
Male, Models, Molecular, Snake venom, Protein Conformation, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Plasmodium falciparum, Mutant, Sequence Homology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Virus Replication, Biochemistry, Phospholipases A, Article, 03 medical and health sciences, Phospholipase A2, Protein structure, Escherichia coli, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Peptide sequence, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Sequence Homology, Amino Acid, biology, 030302 biochemistry & molecular biology, Neurotoxicity, HIV, Active site, medicine.disease, Phospholipases A2, Enzyme, chemistry, biology.protein, Drosophila, Electrophoresis, Polyacrylamide Gel, Chickens, Snake Venoms
Abstract

Several snake venom secreted phospholipases A2 (sPLA2s) including OS2 exert a variety of pharmacological effects ranging from central neurotoxicity to anti-HIV activity by mechanisms that are not yet fully understood. To conclusively address the role of enzymatic activity and map the key structural elements of OS2 responsible for its pharmacological properties, we have prepared single point OS2 mutants at the catalytic site and large chimeras between OS2 and OS1, a homologous but nontoxic sPLA2. Most importantly, we found that the enzymatic activity of the active site mutant H48Q is 500-fold lower than that of the wild-type protein, while central neurotoxicity is only 16-fold lower, providing convincing evidence that catalytic activity is at most a minor factor that determines central neurotoxicity. The chimera approach has identified the N-terminal region (residues 1-22) of OS2, but not the central one (residues 58-89), as crucial for both enzymatic activity and pharmacological effects. The C-terminal region of OS2 (residues 102-119) was found to be critical for enzymatic activity, but not for central neurotoxicity and anti-HIV activity, allowing us to further dissociate enzymatic activity and pharmacological effects. Finally, direct binding studies with the C-terminal chimera, which poorly binds to phospholipids while it is still neurotoxic, led to the identification of a subset of brain N-type receptors which may be directly involved in central neurotoxicity. UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP)

Published
2006

5. Isolation and characterization of Psalmopeotoxin I and II: two novel antimalarial peptides from the venom of the tarantula Psalmopoeus cambridgei

Author

Marie-Louise Célérier, David M. Ojcius, Carole Guillaume, Jean-Michel Camadro, Romain Parent, Christiane Delarbre, Jean-Jacques Montagne, Soo Jin Choi, Jordi Molgó, Mohamed Amiche, Christiane Deregnaucourt, Catherine Guette, Aude Phelipot, Laboratoire d'Ingénierie des Protéines et Contrôle Métabolique, Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie et biochimie des substances naturelles, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Molécules de Communication et Adaptation des Micro-Organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Immunologie Cellulaire, Laboratoire Ecologie et évolution, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Laboratoire de Bioactivation des Peptides, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de neurobiologie cellulaire et moléculaire (NBCM), Institut de Neurobiologie Alfred Fessard (INAF), École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: Sequence Homology, Amino Acid, Psalmopoeus cambridgei, Neuromuscular transmission, Spider Venoms, Peptide, Venom, MESH: Amino Acid Sequence, MESH: Base Sequence, Biochemistry, Structural Biology, MESH: Animals, Conserved Sequence, MESH: Plasmodium falciparum, chemistry.chemical_classification, 0303 health sciences, MESH: Conserved Sequence, biology, 030302 biochemistry & molecular biology, Rana esculenta, Spiders, MESH: Spider Venoms, 3. Good health, MESH: Rana esculenta, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Signal peptide, Molecular Sequence Data, Plasmodium falciparum, Biophysics, Neuromuscular Junction, MESH: Sequence Alignment, MESH: Spiders, 03 medical and health sciences, Antimalarials, Genetics, Animals, Amino Acid Sequence, Molecular Biology, 030304 developmental biology, MESH: Molecular Sequence Data, Base Sequence, Sequence Homology, Amino Acid, Tarantula venom, Cell Biology, biology.organism_classification, Molecular biology, MESH: Antimalarials, In vitro, MESH: Male, Malaria, ICK peptide, chemistry, MESH: Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Inhibitor cystine knot, MESH: Neuromuscular Junction, Sequence Alignment
Abstract

Two novel peptides that inhibit the intra-erythrocyte stage of Plasmodium falciparum in vitro were identified in the venom of the Trinidad chevron tarantula, Psalmopoeus cambridgei. Psalmopeotoxin I (PcFK1) is a 33-residue peptide and Psalmopeotoxin II (PcFK2) has 28-amino acid residues; both have three disulfide bridges and belong to the Inhibitor Cystine Knot superfamily. The cDNAs encoding both peptides were cloned, and nucleotide sequence analysis showed that the peptides are synthesized with typical signal peptides and pro-sequences that are cleaved at a basic doublet before secretion of the mature peptides. The IC(5O) of PcFK1 for inhibiting P. falciparum growth was 1.59+/-1.15 microM and that of PcFK2 was 1.15+/-0.95 microM. PcFK1 was adsorbed strongly to uninfected erythrocytes, but PcFK2 was not. Neither peptide has significant hemolytic activity at 10 microM. Electrophysiological recordings in isolated frog and mouse neuromuscular preparations revealed that the peptides (at up to 9.3 microM) do not affect neuromuscular transmission or quantal transmitter release. PcFK1 and PcFK2 do not affect the growth or viability of human epithelial cells, nor do they have any antifungal or antibacterial activity at 20 microM. Thus, PcFK1 and PcFK2 seem to interact specifically with infected erythrocytes. They could therefore be promising tools for antimalaria research and be the basis for the rational development of antimalarial drugs.

Published
2004
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