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3. Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening

Author

Carucci, Mario, Duez, Julien, Tarning, Joel, García-Barbazán, Irene, Fricot-Monsinjon, Aurélie, Sissoko, Abdoulaye, Dumas, Lucie, Gamallo, Pablo, Beher, Babette, Amireault, Pascal, Dussiot, Michael, Dao, Ming, Hull, Mitchell V., McNamara, Case W., Roussel, Camille, Ndour, Papa Alioune, Sanz, Laura Maria, Gamo, Francisco Javier, and Buffet, Pierre

Published
2023
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4. Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening

Author

Mario Carucci, Julien Duez, Joel Tarning, Irene García-Barbazán, Aurélie Fricot-Monsinjon, Abdoulaye Sissoko, Lucie Dumas, Pablo Gamallo, Babette Beher, Pascal Amireault, Michael Dussiot, Ming Dao, Mitchell V. Hull, Case W. McNamara, Camille Roussel, Papa Alioune Ndour, Laura Maria Sanz, Francisco Javier Gamo, and Pierre Buffet

Subjects
Science
Abstract

Authors propose their splenic mimetic filtration method, microsphiltration, and utilise this approach in a drug-screen, to identify compounds that induce a stiffening effect on Plasmodium falciparum-infected erythrocytes. They proceed to assess safety and tolerability of one identified compound in a phase I clinical trial.

Published
2023
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6. Sources of variation of DNA methylation in rainbow trout: combined effects of temperature and genetic background

Author

Delphine Lallias, Maria Bernard, Céline Ciobotaru, Nicolas Dechamp, Laurent Labbé, Lionel Goardon, Jean-Michel Le Calvez, Marjorie Bideau, Alexandre Fricot, Audrey Prézelin, Mathieu Charles, Marco Moroldo, Xavier Cousin, Olivier Bouchez, Alain Roulet, Edwige Quillet, and Mathilde Dupont-Nivet

Subjects
temperature, epiradseq, dna methylation, dnmt3, rainbow trout, isogenic lines, Genetics, QH426-470
Abstract

Phenotypic plasticity is a key component of the ability of organisms to respond to changing environmental conditions. In this study, we aimed to study the establishment of DNA methylation marks in response to an environmental stress in rainbow trout and to assess whether these marks depend on the genetic background. The environmental stress chosen here was temperature, a known induction factor of epigenetic marks in fish. To disentangle the role of epigenetic mechanisms such as DNA methylation in generating phenotypic variations, nine rainbow trout isogenic lines with no genetic variability within a line were used. For each line, half of the eggs were incubated at standard temperature (11°C) and the other half at high temperature (16°C), from eyed-stage to hatching. In order to gain a first insight into the establishment of DNA methylation marks in response to an early temperature regime (control 11°C vs. heated 16°C), we have studied the expression of 8 dnmt3 (DNA methyltransferase) genes, potentially involved in de novo methylation, and analysed global DNA methylation in the different rainbow trout isogenic lines using LUMA (LUminometric Methylation Assay). Finally, finer investigation of genome-wide methylation patterns was performed using EpiRADseq, a reduced-representation library approach based on the ddRADseq (Double Digest Restriction Associated DNA) protocol, for six rainbow trout isogenic lines. We have demonstrated that thermal history during embryonic development alters patterns of DNA methylation, but to a greater or lesser extent depending on the genetic background.

Published
2021
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7. Retention of uninfected red blood cells causing congestive splenomegaly is the major mechanism of anemia in malaria

Author

Kho, Steven, primary, Siregar, Nurjati C., additional, Qotrunnada, Labibah, additional, Fricot, Aurélie, additional, Sissoko, Abdoulaye, additional, Shanti, Putu A. I., additional, Candrawati, Freis, additional, Kambuaya, Noy N., additional, Rini, Hasrini, additional, Andries, Benediktus, additional, Hardy, David, additional, Margyaningsih, Nur I., additional, Fadllan, Fauziyah, additional, Rahmayenti, Desandra A., additional, Puspitasari, Agatha M., additional, Aisah, Amelia R., additional, Leonardo, Leo, additional, Yayang, Bagus T. G., additional, Margayani, Dewi S., additional, Prayoga, Pak, additional, Trianty, Leily, additional, Kenangalem, Enny, additional, Price, Ric N., additional, Yeo, Tsin W., additional, Minigo, Gabriela, additional, Noviyanti, Rintis, additional, Poespoprodjo, Jeanne R., additional, Anstey, Nicholas M., additional, and Buffet, Pierre A., additional

Published
2023
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8. Reduced splenic function can mimic artemisinin resistance in severe malaria

Author

Roussel, Camille, primary, Serris, Alexandra, additional, Henry, Benoît, additional, Desmurs, Barthelemy Lafon, additional, Sitterlé, Emilie, additional, Bougnoux, Marie Elisabeth, additional, Argy, Nicolas, additional, Larréché, Sébastien, additional, De Montalembert, Mariane, additional, Ioos, Vincent, additional, Tantaoui, Ilhame, additional, Chambrion, Charlotte, additional, Fricot, Aurélie, additional, Rouzaud, Claire, additional, Lanternier, Fanny, additional, Lortholary, Olivier, additional, Houzé, Sandrine, additional, Jauréguiberry, Stéphane, additional, Thellier, Marc, additional, Ndour, Papa Alioune, additional, and Buffet, Pierre, additional

Published
2023
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9. CO4-6 Le stockage pré-transfusionnel endommage principalement une sous-population érythrocytaire morphologiquement altérée

Author

Peltier, Sandy, primary, Marin, Mickaël, additional, Kalani Roy, Micaela, additional, Dussiot, Michaël, additional, Bruce, Johanna, additional, Hadjou, Youcef, additional, Georgeault, Sonia, additional, Fricot, Aurélie, additional, Roussel, Camille, additional, Dzieciatkowska, Monika, additional, Casimir, Madeleine, additional, Paye, François, additional, Dokmak, Safi, additional, Alioune Ndour, Papa, additional, Roingeard, Philippe, additional, Gautier, Emilie-Fleur, additional, Spitalnik, Steven L, additional, Hermine, Olivier, additional, Buffet, Pierre A, additional, d'Alessandro, Angelo, additional, and Amireault, Pascal, additional

Published
2023
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11. Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: A prospective human splenectomy study.

Author

Steven Kho, Labibah Qotrunnada, Leo Leonardo, Benediktus Andries, Putu A I Wardani, Aurelie Fricot, Benoit Henry, David Hardy, Nur I Margyaningsih, Dwi Apriyanti, Agatha M Puspitasari, Pak Prayoga, Leily Trianty, Enny Kenangalem, Fabrice Chretien, Valentine Brousse, Innocent Safeukui, Hernando A Del Portillo, Carmen Fernandez-Becerra, Elamaran Meibalan, Matthias Marti, Ric N Price, Tonia Woodberry, Papa A Ndour, Bruce M Russell, Tsin W Yeo, Gabriela Minigo, Rintis Noviyanti, Jeanne R Poespoprodjo, Nurjati C Siregar, Pierre A Buffet, and Nicholas M Anstey

Subjects
Medicine
Abstract

BackgroundA very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival.Methods and findingsWe examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted.ConclusionsImmature CD71+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen.

Published
2021
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12. A spin pump turnstile: parametric pumping of a spin-polarized current through a nearly-closed quantum dot

Author

Blaauboer, M. and Fricot, C. M. L.

Subjects
Condensed Matter - Mesoscale and Nanoscale Physics
Abstract

We investigate parametric pumping of a spin-polarized current through a nearly-closed quantum dot in a perpendicular magnetic field. Pumping is achieved by tuning the tunnel couplings to the left and right lead - thereby operating the quantum dot as a turnstile - and changing either the magnetic field or a gate-voltage. We analyze the quantum dynamics of a pumping cycle and the limiting time scales for operating the quantum dot turnstile as a pure spin pump. The proposed device can be used as a fully controllable double-sided and bipolar spin filter and to inject spins "on demand"., Comment: 5 pages, 2 figures, one reference corrected

Published
2004
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13. A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease

Author

James G. McArthur, Niels Svenstrup, Chunsheng Chen, Aurelie Fricot, Caroline Carvalho, Julia Nguyen, Phong Nguyen, Anna Parachikova, Fuad Abdulla, Gregory M. Vercellotti, Olivier Hermine, Dave Edwards, Jean-Antoine Ribeil, John D. Belcher, and Thiago T. Maciel

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

The most common treatment for patients with sickle cell disease (SCD) is the chemotherapeutic hydroxyurea, a therapy with pleiotropic effects, including increasing fetal hemoglobin (HbF) in red blood cells and reducing adhesion of white blood cells to the vascular endothelium. Hydroxyurea has been proposed to mediate these effects through a mechanism of increasing cellular cGMP levels. An alternative path to increasing cGMP levels in these cells is through the use of phosphodiesterase-9 inhibitors that selectively inhibit cGMP hydrolysis and increase cellular cGMP levels. We have developed a novel, potent and selective phosphodiesterase-9 inhibitor (IMR-687) specifically for the treatment of SCD. IMR-687 increased cGMP and HbF in erythroid K562 and UT-7 cells and increased the percentage of HbF positive erythroid cells generated in vitro using a two-phase liquid culture of CD34+ progenitors from sickle cell blood or bone marrow. Oral daily dosing of IMR-687 in the Townes transgenic mouse SCD model, increased HbF and reduced red blood cell sickling, immune cell activation and microvascular stasis. The IMR-687 reduction in red blood cell sickling and immune cell activation was greater than that seen with physiological doses of hydroxyurea. In contrast to other described phosphodiesterase-9 inhibitors, IMR-687 did not accumulate in the central nervous system, where it would inhibit phosphodiesterase-9 in neurons, or alter rodent behavior. IMR-687 was not genotoxic or myelotoxic and did not impact fertility or fetal development in rodents. These data suggest that IMR-687 may offer a safe and effective oral alternative for hydroxyurea in the treatment of SCD.

Published
2020
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14. Retention of uninfected red blood cells causing congestive splenomegaly is the major mechanism of anemia in malaria.

Author

Kho, Steven, Siregar, Nurjati C., Qotrunnada, Labibah, Fricot, Aurélie, Sissoko, Abdoulaye, Shanti, Putu A. I., Candrawati, Freis, Kambuaya, Noy N., Rini, Hasrini, Andries, Benediktus, Hardy, David, Margyaningsih, Nur I., Fadllan, Fauziyah, Rahmayenti, Desandra A., Puspitasari, Agatha M., Aisah, Amelia R., Leonardo, Leo, Yayang, Bagus T. G., Margayani, Dewi S., and Prayoga, Pak

Published
2024
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16. Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: A prospective human splenectomy study

Author

Kho, Steven, Qotrunnada, Labibah, Leonardo, Leo, Andries, Benediktus, Wardani, Putu A. I., Fricot, Aurelie, Henry, Benoit, Hardy, David, Margyaningsih, Nur I., Apriyanti, Dwi, Puspitasari, Agatha M., Prayoga, Pak, Trianty, Leily, Kenangalem, Enny, Chretien, Fabrice, Brousse, Valentine, Safeukui, Innocent, del Portillo, Hernando A., Fernandez-Becerra, Carmen, Meibalan, Elamaran, Marti, Matthias, Price, Ric N., Woodberry, Tonia, Ndour, Papa A., Russell, Bruce M., Yeo, Tsin W., Minigo, Gabriela, Noviyanti, Rintis, Poespoprodjo, Jeanne R., Siregar, Nurjati C., Buffet, Pierre A., and Anstey, Nicholas M.

Subjects
Spleen -- Health aspects -- Physiological aspects, Plasmodium vivax -- Physiological aspects, Erythrocytes -- Health aspects -- Physiological aspects, Malaria -- Physiological aspects -- Complications and side effects, Carrier state (Communicable diseases) -- Physiological aspects -- Complications and side effects, Host-parasite relationships -- Physiological aspects, Biological sciences
Abstract

Background A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival. Methods and findings We examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted. Conclusions Immature CD71.sup.+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen., Author(s): Steven Kho 1, Labibah Qotrunnada 2, Leo Leonardo 3, Benediktus Andries 3, Putu A. I. Wardani 4, Aurelie Fricot 5, Benoit Henry 5, David Hardy 6, Nur I. Margyaningsih [...]

Published
2021
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17. Erythrocytic vacuoles that accumulate a fluorescent dye predict spleen size and function in sickle cell disease

Author

Abdoulaye Sissoko, Aurélie Fricot‐Monsinjon, Camille Roussel, Sandra Manceau, Lucie Dumas, Carmen Capito, Slimane Allali, Narjis Yekkache, Michael Dussiot, Yann Nguyen, Agnès Lefort Des Ylouses, Béatrice Aussilhou, Magali Tichit, David Hardy, Blandine Maître, Anita Eckly, Mariane De Montalembert, Marina Cavazzana, Laure Joseph, Pierre Buffet, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications (ERL 8254), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Biologie et Pharmacologie des Plaquettes sanguines : hémostase, thrombose, transfusion (BPP), Université de Strasbourg (UNISTRA)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-20-CE17-0024,SpleenMark,Marqueurs de fonction splénique pour la pratique médicale(2020)

Subjects
Erythrocytes, [SDV]Life Sciences [q-bio], Vacuoles, Humans, Anemia, Sickle Cell, Hematology, Spleen, Fluorescent Dyes
Abstract

International audience

Published
2022

18. Erythrocytic vacuoles that accumulate a fluorescent dye predict spleen size and function in sickle cell disease

Author

Sissoko, Abdoulaye, primary, Fricot‐Monsinjon, Aurélie, additional, Roussel, Camille, additional, Manceau, Sandra, additional, Dumas, Lucie, additional, Capito, Carmen, additional, Allali, Slimane, additional, Yekkache, Narjis, additional, Dussiot, Michael, additional, Nguyen, Yann, additional, Lefort Des Ylouses, Agnès, additional, Aussilhou, Béatrice, additional, Tichit, Magali, additional, Hardy, David, additional, Maître, Blandine, additional, Eckly, Anita, additional, De Montalembert, Mariane, additional, Cavazzana, Marina, additional, Joseph, Laure, additional, and Buffet, Pierre, additional

Published
2022
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19. Splenic clearance of rigid erythrocytes as an inherited mechanism for splenomegaly and natural resistance to malaria

Author

Benoît Henry, Geoffroy Volle, Hilaire Akpovi, Laure Gineau, Camille Roussel, Papa Alioune Ndour, Félicien Tossou, Felipe Suarez, Friso Palstra, Aurélie Fricot, Charlotte Chambrion, Julien Solinc, Julie Nguyen, Mathilde Garé, Florentin Aussenac, Charles-Henry Cottart, Christine Keyser, Rafiou Adamou, Magali Tichit, David Hardy, Nadine Fievet, Jérôme Clain, André Garcia, David Courtin, Olivier Hermine, Audrey Sabbagh, Pierre Buffet, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Institut National de la Transfusion Sanguine [Paris] (INTS), Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Bicêtre, Centre d’Etude et de Recherche sur les Pathologies Associéees à la Grossesse et à l’Enfance [Cotonou, Bénin] (CERPAGE), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), Centre Interfacultaire de Formation et de Recherche en Environnement pour le Développement Durable [Cotonou, Benin] (CIFRED), Université d’Abomey-Calavi = University of Abomey Calavi (UAC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie, anthropologie, biométrie, épigénétique, lignées : De la diversité des populations à l'individu, de l'identification à l'identité (BABEL), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), This research was supported by a grant from Labex GR-Ex and from the National Geographic Society Committee for Research and Exploration (Grant 9804-15). The labex GR-Ex, reference ANR-11-LABX-0051 is funded by the program Investissements d'avenir of the French National Research Agency, reference ANR-11-IDEX-0005-02. It also received funding from IMEA (Institut de Médecine et d'Epidémiologie Appliquée) and IRD (Institut de Recherche pour le Développement), BH was supported by a grant from Région Ile de France (DIM Malinf, grant dim150030)., ANR-11-LABX-0051,GR-Ex,Biogenèse et pathologies du globule rouge(2011), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Hardy, David, Biogenèse et pathologies du globule rouge - - GR-Ex2011 - ANR-11-LABX-0051 - LABX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, and Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216)

Subjects
Falciparum, Genome-wide association study, Erythrocytes, Phosphoric Diester Hydrolases, [SDV]Life Sciences [q-bio], Plasmodium falciparum, Membrane Proteins, RNA-Binding Proteins, Anemia, General Medicine, Ethnic groups, General Biochemistry, Genetics and Molecular Biology, Immunity, Innate, Malaria, [SDV] Life Sciences [q-bio], Cohort Studies, DNA-Binding Proteins, Heritability, Immunoglobulin M, Splenomegaly, Humans, Malaria, Falciparum, Spleen
Abstract

In malaria-endemic areas, subjects from specific groups like Fulani have a peculiar protection against malaria, with high levels of IgM but also frequent anemia and splenomegaly. The mechanisms underlying this phenotype remain elusive. In Benin, West Africa, we measured the deformability of circulating erythrocytes in genetically distinct groups (including Fulani) living in sympatry, using ektacytometry and microsphiltration, a mimic of how the spleen clears rigid erythrocytes. Compared to non-Fulani, Fulani displayed a higher deformability of circulating erythrocytes, pointing to an enhanced clearance of rigid erythrocytes by the spleen. This phenotype was observed in individuals displaying markers of Plasmodium falciparum infection. The heritability of this new trait was high, with a strong multigenic component. Five of the top 10 genes selected by a population structure-adjusted GWAS, expressed in the spleen, are potentially involved in splenic clearance of erythrocytes (CHERP, MB, PALLD, SPARC, PDE10A), through control of vascular tone, collagen synthesis and macrophage activity. In specific ethnic groups, genetically-controlled processes likely enhance the innate retention of infected and uninfected erythrocytes in the spleen, explaining splenomegaly, anemia, cryptic intrasplenic parasite loads, hyper-IgM, and partial protection against malaria. Beyond malaria-related phenotypes, inherited splenic hyper-filtration of erythrocytes may impact the pathogenesis of other hematologic diseases.Research in contextEvidence before this studyThe genetic background of individuals influences their susceptibility to infectious diseases. Specific human groups, like the Fulani in Africa, react to malaria parasites (named Plasmodium) in a specific way. Upon infection, Fulani develop a grossly enlarged spleen, and high levels of anti-Plasmodium antibodies in their blood. They also carry smaller numbers of parasites in their blood, and thus are considered partially protected against malaria. The mechanisms underlying this natural protection, different from other natural protective mechanisms such as the sickle cell trait, are not well understood.Malaria impairs the deformability of red blood cells and the spleen is a key organ to controlling red blood cell quality. We have recently demonstrated that red blood cells containing live malaria parasites accumulate intensely in the spleen of subjects with long term exposure to these parasites. Enhanced retention of infected and uninfected red blood cells in the spleen would explain why the spleen is larger and why lower numbers of parasites are left in circulation. We thus explored whether the retention of infected and uninfected red blood cells could explain why Fulani are partially protected against malaria. Because it is unethical to perform spleen puncture or biopsies for research purposes, our explorations were indirect by carefully analyzing the properties of circulating red blood cells in a large number of subjects and by assessing whether observations could be explained by their genetic make-up.Added value of this studyIn more than 500 subjects, we confirmed the high frequency of large spleens in Fulani and, through 2 different methods, we demonstrated an enhanced deformability of their circulating red blood cells, that likely stems from the more efficient removal of the less deformable ones. This enhanced deformability was found to be inheritable based on carefully collected family links and refined analysis of genetic markers.Implications of all the available evidenceOur findings indicate that genes potentially driving the filtration of red blood cells by the spleen likely influence how subjects in specific groups in Africa and elsewhere react to malaria. While most previous hypotheses pointed to conventional immunological mechanisms as the trigger, we propose that a simple physiological mechanism that controls the quality of red blood cells may drive natural protection from malaria even before the intervention of immunological cells. A better understanding of these processes is of great importance in the context of malaria elimination efforts.These findings may also have an impact on the understanding of other red blood cell-related disorders, such as inherited red cell diseases, in which splenic filtration of abnormal red blood cells may precipitate splenic complications.

Published
2022

22. O-11: AUTOMATED QUANTIFICATION OF POCKED RED BLOOD CELLS CORRELATES WITH SPLEEN SIZE IN SICKLE CELL DISEASE

Author

A., SISSOKO, primary, A., FRICOT, additional, C., ROUSSEL, additional, S., MANCEAU, additional, L., DUMAS, additional, C., CAPITO, additional, S., ALLALI, additional, N., YEKKACHE, additional, M., DUSSIOT, additional, Y., NGUYEN, additional, A., LEFORT, additional, B., AUSSILHOU, additional, M., TICHIT, additional, D., HARDY, additional, B., MAÎTRE, additional, A., MICHEL, additional, M., DE MONTALEMBERT, additional, M., CAVAZZANA, additional, L., JOSEPH, additional, and P., BUFFET, additional

Published
2022
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23. P-061: DE NOVO APPEARANCE OF VACUOLES IN TRANSFUSED RED BLOOD CELLS IN SICKLE CELL DISEASE PATIENTS WITH DEFECTIVE SPLENIC FUNCTION

Author

L., DUMAS, primary, A., SISSOKO, additional, A., FRICOT, additional, N., SALAMA, additional, L., JOSEPH, additional, S., MANCEAU, additional, S., DOKMAK, additional, A., MICHEL, additional, B., MAITRE, additional, C., GACHET, additional, M., CAVAZZANA, additional, C., ROUSSEL, additional, and P., BUFFET, additional

Published
2022
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24. Splenic clearance of rigid erythrocytes as an inherited mechanism for splenomegaly and natural resistance to malaria

Author

Henry, Benoît, primary, Volle, Geoffroy, additional, Akpovi, Hilaire, additional, Gineau, Laure, additional, Roussel, Camille, additional, Ndour, Papa Alioune, additional, Tossou, Félicien, additional, Suarez, Felipe, additional, Palstra, Friso, additional, Fricot, Aurélie, additional, Chambrion, Charlotte, additional, Solinc, Julien, additional, Nguyen, Julie, additional, Garé, Mathilde, additional, Aussenac, Florentin, additional, Cottart, Charles-Henry, additional, Keyser, Christine, additional, Adamou, Rafiou, additional, Tichit, Magali, additional, Hardy, David, additional, Fievet, Nadine, additional, Clain, Jérôme, additional, Garcia, André, additional, Courtin, David, additional, Hermine, Olivier, additional, Sabbagh, Audrey, additional, and Buffet, Pierre, additional

Published
2022
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25. P1496: OPERATOR-INDEPENDENT, FLUORESCENCE-BASED QUANTIFICATION OF POCKED RED CELLS CORRELATES WITH SPLEEN SIZE AND FUNCTION IN SICKLE CELL DISEASE

Author

Sissoko, A., primary, Fricot, A., additional, Dumas, L., additional, Roussel, C., additional, Manceau, S., additional, Capito, C., additional, Allali, S., additional, Yekkache, N., additional, Dussiot, M., additional, NGUYEN, Y., additional, Lefort, A., additional, Aussilhou, B., additional, Tichit, M., additional, Hardy, D., additional, Maître, B., additional, Michel, A., additional, De Montalembert, M., additional, Cavazzana, M., additional, Joseph, L., additional, and Buffet, P., additional

Published
2022
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27. Altered Subpopulations of Red Blood Cells and Post-treatment Anemia in Malaria

Author

Charlotte Chambrion, Mallorie Depond, Lucia Angella, Oussama Mouri, Eric Kendjo, Aurélie Fricot-Monsinjon, Camille Roussel, Sylvestre Biligui, Ilhame Tantaoui, Aida Taieb, Nicolas Argy, Sandrine Houzé, Renaud Piarroux, Jean-Yves Siriez, Stéphane Jaureguiberry, Sébastien Larréché, Marc Théllier, Nicolas Cenac, Pierre Buffet, Papa Alioune Ndour, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Centre National de Référence du Paludisme [CHU Pitié-Salpétrière] (CNRpalu), CHU Pitié-Salpêtrière [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), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Hôpital Robert Debré Paris, Hôpital Robert Debré, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), French Ministry of Research, GR-Ex laboratory of excellence, ANR-18-CE17-0018,PHeSMalEBiPPP,Anémie hémolytique post-traitement dans le paludisme grave: Elucidation de la clairance biomécanique des globules rouges pittés pour la prédiction et la prévention(2018), SEGUIN, Nathalie, and APPEL À PROJETS GÉNÉRIQUE 2018 - Anémie hémolytique post-traitement dans le paludisme grave: Elucidation de la clairance biomécanique des globules rouges pittés pour la prédiction et la prévention - - PHeSMalEBiPPP2018 - ANR-18-CE17-0018 - AAPG2018 - VALID

Subjects
membrane lipid balance, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Physiology, pitted or once infected RBC, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], artemisinin derivatives, falcipaprum, RBC deformability, spleen filtering funcion, Physiology (medical), malaria anemia, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

In acute malaria, the bulk of erythrocyte loss occurs after therapy, with a nadir of hemoglobin generally observed 3–7 days after treatment. The fine mechanisms leading to this early post-treatment anemia are still elusive. We explored pathological changes in RBC subpopulations by quantifying biochemical and mechanical alterations during severe malaria treated with artemisinin derivatives, a drug family that induce “pitting” in the spleen. In this study, the hemoglobin concentration dropped by 1.93 G/dl during therapy. During the same period, iRBC accounting for 6.12% of all RBC before therapy (BT) were replaced by pitted-RBC, accounting for 5.33% of RBC after therapy (AT). RBC loss was thus of 15.9%, of which only a minor part was due to the loss of iRBC or pitted-RBC. When comparing RBC BT and AT to normal controls, lipidomics revealed an increase in the cholesterol/phosphatidylethanolamine ratio (0.17 versus 0.24, p < 0.001) and cholesterol/phosphatidylinositol ratio (0.36 versus 0.67, p = 0.001). Using ektacytometry, we observed a reduced deformability of circulating RBC, similar BT and AT, compared to health control donors. The mean Elongation Index at 1.69Pa was 0.24 BT and 0.23 AT vs. 0.28 in controls (p < 0.0001). At 30Pa EI was 0.56 BT and 0.56 AT vs. 0.60 in controls (p < 0.001). The retention rate (rr) of RBC subpopulations in spleen-mimetic microsphere layers was higher for iRBC (rr = 20% p = 0.0033) and pitted-RBC (rr = 19%, p = 0.0031) than for healthy RBC (0.12%). Somewhat surprisingly, the post-treatment anemia in malaria results from the elimination of RBC that were never infected.

Published
2022
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30. Altered Subpopulations of Red Blood Cells and Post-treatment Anemia in Malaria

Author

Chambrion, Charlotte, primary, Depond, Mallorie, additional, Angella, Lucia, additional, Mouri, Oussama, additional, Kendjo, Eric, additional, Fricot-Monsinjon, Aurélie, additional, Roussel, Camille, additional, Biligui, Sylvestre, additional, Tantaoui, Ilhame, additional, Taieb, Aida, additional, Argy, Nicolas, additional, Houzé, Sandrine, additional, Piarroux, Renaud, additional, Siriez, Jean-Yves, additional, Jaureguiberry, Stéphane, additional, Larréché, Sébastien, additional, Théllier, Marc, additional, Cenac, Nicolas, additional, Buffet, Pierre, additional, and Ndour, Papa Alioune, additional

Published
2022
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31. La céramique médiévale et moderne du bassin de la Loire moyenne, chrono-typologie et transformation des aires culturelles dans la longue durée (6e—19e s.)

Author

Philippe Husi, Lise Bellanger, Arthur Coulon, Viviane Aubourg, Anne Bocquet, Jérôme Bouillon, Marine Bonnard, Emmanuelle Coffineau, Alexandra Finet, Ludovic Fricot, Magali Gary, Claire Gerbaud, Etienne Jaffrot, Sébastien Jesset, Didier Josset, Marie-Christine Lacroix, Coline Lejault, Chloée Leparmentier, Alexandre Longelin, Flore Marteaux, Sébastien Millet, Isabelle Moréra-Vinçotte, Aurore Noël, Clément Rigault, Testard Pierre, Brigitte Véquaud, Husi, Philippe, Modèle explicatif de la fabrique urbaine d'Angkor Thom : archéologie d'une capitale disparue - - ModAThom2017 - ANR-17-CE27-0008 - AAPG2017 - VALID, Laboratoires d'excellence - Centre de Mathématiques Henri Lebesgue : fondements, interactions, applications et Formation - - LEBESGUE2011 - ANR-11-LABX-0020 - LABX - VALID, and FERAC

Subjects
Moyen Âge, mécanisme socio-économique, [SHS.ARCHEO] Humanities and Social Sciences/Archaeology and Prehistory, Méthodes et outils statistiques, Céramologie, Bassin de la Loire moyenne, époque moderne et contemporaine, [STAT] Statistics [stat], Archéologie, package R, Centre-Ouest de la France, aires culturelles, poterie, céramique
Abstract

La présente publication, en accès libre sur Huma-Num, résulte d’un Projet Collectif de Recherche (PCR) sur la céramique médiévale et moderne du bassin de la Loire moyenne qui s’inscrit dans la longue durée, puisqu’il a commencé en 1996 et a déjà fait l’objet de deux suppléments à la RACF (Husi 2003 dir. https://www.persee.fr/issue/sracf_1159-7151_2003_ant1 et Husi 2013 dir. https://journals.openedition.org/racf/1860).Cette publication a comme objectif d’appréhender : (i) la question de la chronologie à partir d’une démarche archéo-statistique originale ; (ii) les questions économiques sociales et culturelles notamment liées aux traditions de fabrication, aux flux et aux échanges de récipients au sein et à l’extérieur de l’espace retenu et dans la longue durée (6e-19e s.) ; (iii) la question de la pertinence de la céramique comme source essentielle de la culture matérielle, comme indicateur fonctionnel des sites et social des habitants.Nous avons fait ici le choix d’un format de publication logiciste dont l’originalité est de proposer une lecture rapide et à plusieurs niveaux du raisonnement, des résultats et de l’argumentaire à partir d’une masse importante de données. En effet, l’analyse logiciste est fondée sur des opérations logiques, dites d’inférence, à double lecture, dans un sens sur un raisonnement empirico-inductif d’inférence par généralisation des observations et dans l’autre sur un raisonnement hypothético-déductif d’inférence déduite des prémisses, excluant de fait des textes longs et descriptifs.L’architecture de la publication s’articule autour de sept grands blocs qui se déclinent de la manière suivante : (Bloc 1) La chronologie, préalable indispensable à tout discours historique, construite à partir d'une démarche archéo-statistique originale aboutissant à une périodisation générale des sites et des ensembles à l’origine de la chrono-typologie de la céramique ; (Bloc 2) les diagrammes logicistes subdivisés en deux sections, représentent graphiquement la structure arborescente des chaînes d’inférence entre les propositions logicistes ; (Bloc 3) une suite de propositions logicistes fondées sur l’analyse commentée des données primaires, introduites pour chacune des deux sections par un court texte de synthèse des résultats historiques ; (Bloc 4) les méthodes archéo-statistiques élaborées pour analyser un corpus de données volumineux ; (Bloc 5) les planches chrono-typologiques de synthèse réalisées par sous-espaces constitutifs du bassin de la Loire moyenne et les répertoires typologiques ; (Bloc 6) les données mobilisées dans le cadre de cette publication ; (Bloc 7) deux études thématiques abordant (i) la question des périodes de transition (ii) un type de récipient particulier, les cloches de cuisson en terre cuite chamottée.Enfin sont présentées les notices de sites et d’assemblages céramiques comprenant une rapide explication du contexte archéologique, les planches de dessins et l’accès aux données pour chaque assemblage. Bien que volumineux, donc quelque peu en contradiction avec le choix d’une publication logiciste, ce chapitre doit être perçu comme un ensemble d’informations supplémentaires à la lecture de la publication logiciste.Les méthodes archéo-statistiques élaborées pour l’analyse de données mobilière volumineuses sont développées dans le cadre du projet interdisciplinaire SPARTAAS, collaboration entre le laboratoire Archéologie et Territoires (UMR CITERES-LAT, CNRS/Université de Tours) et le laboratoire de mathématiques de l’Université de Nantes (UMR LMJL, CNRS/Université de Nantes). Outre l’usage fréquent de liens hypertextes mettant en relation des différents blocs, la publication se réfère également à la base de données en ligne du réseau d’information sur la céramique médiévale et moderne ICERAMM.

Published
2022

35. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia

Author

Dussiot, Michael, Maciel, Thiago T., Fricot, Aurelie, Chartier, Celine, Negre, Olivier, Veiga, Joel, Grapton, Damien, Paubelle, Etienne, Payen, Emmanuel, Beuzard, Yves, Leboulch, Philippe, Ribeil, Jean-Antoine, Arlet, Jean-Benoit, Cote, Francine, Courtois, Genevieve, Ginzburg, Yelena Z., Daniel, Thomas O., Chopra, Rajesh, Sung, Victoria, Hermine, Olivier, and Moura, Ivan C.

Subjects
Cytokines -- Physiological aspects -- Genetic aspects -- Research, Erythropoiesis -- Physiological aspects -- Genetic aspects -- Research, Thalassemia -- Development and progression -- Genetic aspects -- Care and treatment -- Research, Biological sciences, Health
Abstract

The pathophysiology of ineffective erythropoiesis in b-thalassemia is poorly understood. We report that RAP-011, an activin receptor IIA (ActRIIA) ligand trap, improved ineffective erythropoiesis, corrected anemia and limited iron overload [...]

Published
2014

36. A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease

Author

Fuad Abdulla, Gregory M. Vercellotti, John D. Belcher, Aurélie Fricot, Caroline Carvalho, Olivier Hermine, Julia Nguyen, Niels Svenstrup, James G. Mcarthur, Anna I. Parachikova, Chunsheng Chen, Dave Edwards, Phong Nguyen, Jean Antoine Ribeil, and Thiago Trovati Maciel

Subjects
Phosphodiesterase Inhibitors, Cell, Anemia, Sickle Cell, Pharmacology, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Fetal hemoglobin, medicine, Animals, Humans, Hydroxyurea, Red Cell Biology & its Disorders, Progenitor cell, Fetal Hemoglobin, Phosphoric Diester Hydrolases, Chemistry, Phosphodiesterase, Hematology, In vitro, Red blood cell, medicine.anatomical_structure, Bone marrow, K562 Cells, 030215 immunology, K562 cells
Abstract

The most common treatment for patients with sickle cell disease (SCD) is the chemotherapeutic hydroxyurea, a therapy with pleiotropic effects, including increasing fetal hemoglobin (HbF) in red blood cells and reducing adhesion of white blood cells to the vascular endothelium. Hydroxyurea has been proposed to mediate these effects through a mechanism of increasing cellular cGMP levels. An alternative path to increasing cGMP levels in these cells is through the use of phosphodiesterase-9 inhibitors that selectively inhibit cGMP hydrolysis and increase cellular cGMP levels. We have developed a novel, potent and selective phosphodiesterase-9 inhibitor (IMR-687) specifically for the treatment of SCD. IMR-687 increased cGMP and HbF in erythroid K562 and UT-7 cells and increased the percentage of HbF positive erythroid cells generated in vitro using a two-phase liquid culture of CD34+ progenitors from sickle cell blood or bone marrow. Oral daily dosing of IMR-687 in the Townes transgenic mouse SCD model, increased HbF and reduced red blood cell sickling, immune cell activation and microvascular stasis. The IMR-687 reduction in red blood cell sickling and immune cell activation was greater than that seen with physiological doses of hydroxyurea. In contrast to other described phosphodiesterase-9 inhibitors, IMR-687 did not accumulate in the central nervous system, where it would inhibit phosphodiesterase-9 in neurons, or alter rodent behavior. IMR-687 was not genotoxic or myelotoxic and did not impact fertility or fetal development in rodents. These data suggest that IMR-687 may offer a safe and effective oral alternative for hydroxyurea in the treatment of SCD.

Published
2019

37. Hidden Biomass of Intact Malaria Parasites in the Human Spleen

Author

Nur I. Margyaningsih, Nicholas M. Anstey, Bruce Russell, Innocent Safeukui, Benediktus Andries, Pak Prayoga, Fabrice Chrétien, Leo Leonardo, Matthias Marti, Carmen Fernandez-Becerra, Tonia Woodberry, David Hardy, Labibah Qotrunnada, Ric N. Price, Dwi Apriyanti, Steven Kho, Nurjati Chairani Siregar, Benoit Henry, Papa Alioune Ndour, Gabriela Minigo, Leily Trianty, Tsin W. Yeo, Pierre Buffet, Hernando A. del Portillo, Aurélie Fricot, Agatha M. Puspitasari, Enny Kenangalem, Rintis Noviyanti, Elamaran Meibalan, Jeanne Rini Poespoprodjo, Putu A. I. Wardani, Menzies School of Health Research [Australia], Charles Darwin University, Eijkman Institute for Molecular Biology [Jakarta], Papuan Health and Community Development Foundation [Timika, Papua Indonesia], Rumah Sakit Umum Daerah Kabupaten Mimika [Timika, Papua, Indonesia], Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris (UP), Institut Pasteur [Paris], University of Notre Dame [Indiana] (UND), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), University of Glasgow, University of Otago [Dunedin, Nouvelle-Zélande], Supported by program grant no. 1037304, by fellowship nos. 1042072 and 1135820, to Dr. Anstey, by a grant (no. 1131932) from Improving Health Outcomes in the Tropical North, and by the Australian Centre of Research Excellence in Malaria Elimination — all through the Australian National Health and Medical Research Council, by a grant from the Institut National de la Santé et de la Recherche Médicale, to Dr. Buffet, by a grant from the Wellcome Trust(no. 099875), to Dr. Poespoprodjo, by a Senior Wellcome Trust Fellowship in Clinical Science award(no. 200909), to Dr. Price, by an Australian Government Postgraduate Award Scholarship, to Dr. Kho, by a Royal Society Wolfson Research Merit award, to Dr. Marti, and by the Australian Department of Foreign Affairs and Trade., Hardy, David, Charles Darwin University [Australia], Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)

Subjects
biology, business.industry, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Splenectomy, Spleen, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, biology.organism_classification, Plasmodium, Asymptomatic, Virology, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, parasitic diseases, medicine, 030212 general & internal medicine, medicine.symptom, business, Malaria, ComputingMilieux_MISCELLANEOUS
Abstract

Malaria and the Spleen In this report, patients living in a malaria-endemic area underwent trauma-related splenectomy. In these asymptomatic patients who were naturally infected with Plasmodium fal...

Published
2021

38. Rapid clearance of storage-induced micro-erythrocytes alters transfusion recovery

Author

Madeleine Casimir, Benoit Henry, Camille Roussel, François Paye, Mickael Marin, Safi Dokmak, Alexandre Morel, Papa Alioune Ndour, Steven L. Spitalnik, Alain Sauvanet, Michael Dussiot, Philippe Roingeard, Pierre Buffet, Martin Colard, Geoffroy Volle, Caroline Le Van Kim, Yves Colin, Anaïs Martinez, Olivier Hermine, Eldad A. Hod, Sonia Georgeault, Aurélie Fricot-Monsinjon, Mallorie Depond, Pascal Amireault, Charlotte Chambrion, Gestionnaire, HAL Sorbonne Université 5, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Transfusion Sanguine [Paris] (INTS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Hépatologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de chirurgie générale et digestive [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Plateforme des Microscopies, Université de Tours (UT), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Columbia University [New York], Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Tours, and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, mice, Immunology, Echinocyte, Spleen, 030204 cardiovascular system & hematology, Biochemistry, perfusion, Andrology, 03 medical and health sciences, 0302 clinical medicine, Blood product, retail clinics, Medicine, 030212 general & internal medicine, transfusion, business.industry, Quality assessment, concentrate dosage form, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, macrophages, medicine.anatomical_structure, spleen, business, Perfusion, Ex vivo, Clearance
Abstract

Permanent availability of red blood cells (RBCs) for transfusion depends on refrigerated storage, during which morphologically altered RBCs accumulate. Among these, a subpopulation of small RBCs, comprising type III echinocytes, spheroechinocytes, and spherocytes and defined as storage-induced microerythrocytes (SMEs), could be rapidly cleared from circulation posttransfusion. We quantified the proportion of SMEs in RBC concentrates from healthy human volunteers and assessed correlation with transfusion recovery, investigated the fate of SMEs upon perfusion through human spleen ex vivo, and explored where and how SMEs are cleared in a mouse model of blood storage and transfusion. In healthy human volunteers, high proportion of SMEs in long-stored RBC concentrates correlated with poor transfusion recovery. When perfused through human spleen, 15% and 61% of long-stored RBCs and SMEs were cleared in 70 minutes, respectively. High initial proportion of SMEs also correlated with high retention of RBCs by perfused human spleen. In the mouse model, SMEs accumulated during storage. Transfusion of long-stored RBCs resulted in reduced posttransfusion recovery, mostly due to SME clearance. After transfusion in mice, long-stored RBCs accumulated predominantly in spleen and were ingested mainly by splenic and hepatic macrophages. In macrophage-depleted mice, splenic accumulation and SME clearance were delayed, and transfusion recovery was improved. In healthy hosts, SMEs were cleared predominantly by macrophages in spleen and liver. When this well-demarcated subpopulation of altered RBCs was abundant in RBC concentrates, transfusion recovery was diminished. SME quantification has the potential to improve blood product quality assessment. This trial was registered at www.clinicaltrials.gov as #NCT02889133.

Published
2021

40. Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia

Author

Coulon, Severine, Dussiot, Michael, Grapton, Damien, Maciel, Thiago Trovati, Wang, Pamella Huey Mei, Callens, Celine, Tiwari, Meetu Kaushik, Agarwal, Saurabh, Fricot, Aurelie, Vandekerckhove, Julie, Tamouza, Houda, Zermati, Yael, Ribei, Jean-Antoine, Djedaini, Kamel, Oruc, Zeliha, Pascal, Virginie, Courtois, Genevieve, Arnulf, Bertrand, Alyanakian, Marie-Alexandra, Mayeux, Patrick, Leanderson, Tomas, Benhamou, Marc, Cogne, Michel, Monteiro, Renato C., Hermine, Olivier, and Moura, Ivan C.

Subjects
Anemia -- Genetic aspects -- Care and treatment -- Research, Erythropoietin -- Physiological aspects -- Genetic aspects -- Research, Immunoglobulin A -- Physiological aspects -- Genetic aspects -- Research, Erythropoiesis -- Physiological aspects -- Genetic aspects -- Research, Biological sciences, Health
Abstract

Anemia because of insufficient production of and/or response to erythropoietin (Epo) is a major complication of chronic kidney disease and cancer. The mechanisms modulating the sensitivity of erythroblasts to Epo remain poorly understood. We show that, when cultured with Epo at suboptimal concentrations, the growth and clonogenic potential of erythroblasts was rescued by transferrin receptor 1 (TfR1)-bound polymeric IgA1 (pIgA1). Under homeostatic conditions, erythroblast numbers were increased in mice expressing human IgA1 compared to control mice. Hypoxic stress of these mice led to increased amounts of pIgA1 and erythroblast expansion. Expression of human IgA1 or treatment of wild-type mice with the TfR1 ligands pIgA1 or iron-loaded transferrin (Fe-Tf) accelerated recovery from acute anemia. TfR1 engagement by either pIgA1 or Fe-Tf increased cell sensitivity to Epo by inducing activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. These cellular responses were mediated through the TfR1-internalization motif, YXXO. Our results show that pIgA1 and TfR1 are positive regulators of erythropoiesis in both physiological and pathological situations. Targeting this pathway may provide alternate approaches to the treatment of ineffective erythropoiesis and anemia., Erythropoiesis relies on the commitment of hematopoietic stem cells to erythroid progenitors and precursors. Stem cell factor (SCF) and Epo are required for the proliferation and survival of erythroid cells [...]

Published
2011
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41. PATHOLOGY INFLAMMATION

Author

Maciel, Thiago Trovati, Merle, Emilie, Fricot, Aurelie, Monteiro, Renato, and Moura, Ivan Cruz

Published
2014

42. Hidden Biomass of Intact Malaria Parasites in the Human Spleen

Author

Kho, Steven, primary, Qotrunnada, Labibah, additional, Leonardo, Leo, additional, Andries, Benediktus, additional, Wardani, Putu A.I., additional, Fricot, Aurelie, additional, Henry, Benoit, additional, Hardy, David, additional, Margyaningsih, Nur I., additional, Apriyanti, Dwi, additional, Puspitasari, Agatha M., additional, Prayoga, Pak, additional, Trianty, Leily, additional, Kenangalem, Enny, additional, Chretien, Fabrice, additional, Safeukui, Innocent, additional, del Portillo, Hernando A., additional, Fernandez-Becerra, Carmen, additional, Meibalan, Elamaran, additional, Marti, Matthias, additional, Price, Ric N., additional, Woodberry, Tonia, additional, Ndour, Papa A., additional, Russell, Bruce M., additional, Yeo, Tsin W., additional, Minigo, Gabriela, additional, Noviyanti, Rintis, additional, Poespoprodjo, Jeanne R., additional, Siregar, Nurjati C., additional, Buffet, Pierre A., additional, and Anstey, Nicholas M., additional

Published
2021
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43. Rapid clearance of storage-induced microerythrocytes alters transfusion recovery

Author

Roussel, Camille, primary, Morel, Alexandre, additional, Dussiot, Michaël, additional, Marin, Mickaël, additional, Colard, Martin, additional, Fricot-Monsinjon, Aurélie, additional, Martinez, Anaïs, additional, Chambrion, Charlotte, additional, Henry, Benoît, additional, Casimir, Madeleine, additional, Volle, Geoffroy, additional, Dépond, Mallorie, additional, Dokmak, Safi, additional, Paye, François, additional, Sauvanet, Alain, additional, Le Van Kim, Caroline, additional, Colin, Yves, additional, Georgeault, Sonia, additional, Roingeard, Philippe, additional, Spitalnik, Steven L., additional, Ndour, Papa Alioune, additional, Hermine, Olivier, additional, Hod, Eldad A., additional, Buffet, Pierre A., additional, and Amireault, Pascal, additional

Published
2021
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44. Feeding status regulates the polyubiquitination step of the ubiquitin-proteasome-dependent proteolysis in rainbow trout (Oncorhynchus mykiss) muscle

Author

Seiliez, Iban, Panserat, Stephane, Skiba-Cassy, Sandrine, Fricot, Aurelie, Vachot, Christiane, Kaushik, Sadasivam, and Tesseraud, Sophie

Subjects
Proteolysis -- Control, Rainbow trout -- Physiological aspects, Rainbow trout -- Food and nutrition, Ubiquitin-proteasome system -- Control, Ubiquitin-proteasome system -- Properties, Animal feeding behavior -- Influence, Food/cooking/nutrition
Abstract

In mammals, the ubiquitin-proteasome proteolytic pathway is a major route of protein degradation and has been shown to be regulated by the feeding status via the protein kinase B (PKB)-Forkehead box-O transcription factor signaling pathwaymediated transcription regulation of atrophy-related ubiquitin ligases, atroginl and muscle RING finger 1. In contrast, in rainbow trout (Oncorhynchus mykiss), the activity of the proteasome in muscle was not affected during starvation-induced muscle degradation. The aim of this study was therefore to explore the molecular basis for this lack of induction of this proteolytic route during starvation. In this study, rainbow trout were food deprived for 7 and 14 d, refed ad libitum, and the effect of the nutritional status was assessed on the different steps involved in the regulation of the ubiquitin-proteasome system in muscle. We observed that starvation reduced the phosphorylation of PKB and enhanced the expression of atroginl in muscle, whereas refeeding led to the opposite effects. The level of polyubiquitinated proteins in muscle increased to over 2 times the initial value on d 0 after 14 d of starvation and decreased significantly at 12 h after refeeding, but there were no major changes in the activity of the main proteasomal peptidases (chymotrypsin-like and trypsin-like). Altogether, these results indicate that in rainbow trout muscle, the polyubiquitination step of the ubiquitin-proteasome route is regulated by the feeding status similarly to what is observed in mammals.

Published
2008

45. Sources of variation of DNA methylation in rainbow trout: combined effects of temperature and genetic background

Author

Alain Roulet, Lionel Goardon, Céline Ciobotaru, Jean-Michel Le Calvez, Maria Bernard, Mathieu Charles, Audrey Prézelin, Marjorie Bideau, Olivier Bouchez, Laurent Labbé, Nicolas Dechamp, Edwige Quillet, Xavier Cousin, Alexandre Fricot, Mathilde Dupont-Nivet, Marco Moroldo, Delphine Lallias, Génétique Animale et Biologie Intégrative (GABI), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Système d'Information des GENomes des Animaux d'Elevage (SIGENAE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Pisciculture Expérimentale INRAE des Monts d'Arrée (PEIMA), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Génome et Transcriptome - Plateforme Génomique ( GeT-PlaGe), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), H2020 European Research Council652831, European Project: 652831,H2020,H2020-INFRAIA-2014-2015,AQUAEXCEL2020(2015), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MARine Biodiversity Exploitation and Conservation (UMR MARBEC), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3)

Subjects
0301 basic medicine, Cancer Research, [SDE.MCG]Environmental Sciences/Global Changes, Embryonic Development, Biology, DNA methyltransferase, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Animals, isogenic lines, 14. Life underwater, Epigenetics, Genetic variability, dnmt3, Molecular Biology, Gene, Genetics, DNA methylation, EpiRADseq, Temperature, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Methylation, rainbow trout, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Oncorhynchus mykiss, Rainbow trout, Genetic Background, DNA, Research Paper
Abstract

International audience; Phenotypic plasticity is a key component of the ability of organisms to respond to changing environmental conditions. In this study, we aimed to study the establishment of DNA methylation marks in response to an environmental stress in rainbow trout and to assess whether these marks depend on the genetic background. The environmental stress chosen here was temperature, a known induction factor of epigenetic marks in fish. To disentangle the role of epigenetic mechanisms such as DNA methylation in generating phenotypic variations, nine rainbow trout isogenic lines with no genetic variability within a line were used. For each line, half of the eggs were incubated at standard temperature (11°C) and the other half at high temperature (16°C), from eyed-stage to hatching. In order to gain a first insight into the establishment of DNA methylation marks in response to an early temperature regime (control 11°C vs. heated 16°C), we have studied the expression of 8 dnmt3 (DNA methyltransferase) genes, potentially involved in de novo methylation, and analysed global DNA methylation in the different rainbow trout isogenic lines using LUMA (LUminometric Methylation Assay). Finally, finer investigation of genome-wide methylation patterns was performed using EpiRADseq, a reduced-representation library approach based on the ddRADseq (Double Digest Restriction Associated DNA) protocol, for six rainbow trout isogenic lines. We have demonstrated that thermal history during embryonic development alters patterns of DNA methylation, but to a greater or lesser extent depending on the genetic background.

Published
2020
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48. Sources of variation of DNA methylation in rainbow trout: combined effects of temperature and genetic background

Author

Lallias, Delphine, primary, Bernard, Maria, additional, Ciobotaru, Céline, additional, Dechamp, Nicolas, additional, Labbé, Laurent, additional, Goardon, Lionel, additional, Le Calvez, Jean-Michel, additional, Bideau, Marjorie, additional, Fricot, Alexandre, additional, Prézelin, Audrey, additional, Charles, Mathieu, additional, Moroldo, Marco, additional, Cousin, Xavier, additional, Bouchez, Olivier, additional, Roulet, Alain, additional, Quillet, Edwige, additional, and Dupont-Nivet, Mathilde, additional

Published
2020
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49. Etude de la variabilité génétique de la méthylation de l'ADN en réponse à un stress de température précoce chez la truite arc-en-ciel

Author

Lallias, Delphine, Fricot, A., Liu, Jingwei, Marandel, Lucie, Dechamp, Nicolas, Ciobotaru, Céline, Le Calvez, Jean-Michel, Bideau, Marjorie, Goardon, Lionel, Labbé, Laurent, Quillet, Edwige, Cousin, Xavier, Dupont-Nivet, Mathilde, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Nutrition, Métabolisme, Aquaculture (NuMéA), Institut National de la Recherche Agronomique (INRA)-Université de Pau et des Pays de l'Adour (UPPA), Pisciculture Expérimentale INRA des Monts d'Arrée (PEIMA), Institut National de la Recherche Agronomique (INRA), and European Project: 652831,H2020,H2020-INFRAIA-2014-2015,AQUAEXCEL2020(2015)

Subjects
salmonidae, oncorhynchus mykiss, [SDV.GEN]Life Sciences [q-bio]/Genetics, stress precoce, choc thermique, [SDV]Life Sciences [q-bio], temperature, stress, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, poisson, variabilite genetique, methylation de l'ADN, [INFO]Computer Science [cs], ComputingMilieux_MISCELLANEOUS, truite arc en ciel
Abstract

National audience

Published
2019

50. Positron emission tomography and magnetic resonance imaging in experimental human malaria to identify organ-specific changes in morphology and glucose metabolism: A prospective cohort study

Author

Rintis Noviyanti, Agatha M. Puspitasari, Papa Alioune Ndour, Nurjati Chairani Siregar, Benediktus Andries, Benoit Henry, Leo Leonardo, Dwi Apriyanti, Fabrice Chrétien, Bruce Russell, Nur I. Margyaningsih, Carmen Fernandez-Becerra, Aurélie Fricot, Matthias Marti, Nicholas M. Anstey, Tsin W. Yeo, Valentine Brousse, Labibah Qotrunnada, Ric N. Price, David Hardy, Pierre Buffet, Hernando A. del Portillo, Leily Trianty, Pak Prayoga, Enny Kenangalem, Elamaran Meibalan, Jeanne Rini Poespoprodjo, Innocent Safeukui, Putu A. I. Wardani, Tonia Woodberry, Steven Kho, Gabriela Minigo, Global and Tropical Health Division [Rocklands, Australia], Menzies School of Health Research [Australia], Charles Darwin University [Australia]-Charles Darwin University [Australia], Eijkman Institute for Molecular Biology [Jakarta], Papuan Health and Community Development Foundation [Timika, Papua Indonesia], Rumah Sakit Umum Daerah Kabupaten Mimika [Timika, Papua, Indonesia], Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), University of Notre Dame [Indiana] (UND), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Institut d’Investigació Germans Trias i Pujol = Germans Trias i Pujol Research Institute (IGTP), Institució Catalana de Recerca i Estudis Avançats (ICREA), Harvard School of Public Health, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), University of Glasgow, University of Oxford, Mahidol University [Bangkok], University of Otago [Dunedin, Nouvelle-Zélande], Universitas Gadjah Mada, Universitas Indonesia (UI ), This work was supported by the Australian National Health and Medical Research Council (Program Grant #1037304, Fellowships to NA [#1042072 and #1135820], and ‘Improving Health Outcomes in the Tropical North (HOTNORTH): A multidisciplinary collaboration [#1131932], and the Australian Centre of Research Excellence in Malaria Elimination), the Paris Ile-de-France Region under « DIM Thérapie génique » and « DIM Maladies Infectieuses » initiatives (awarded to PAB and BH), the French Institut National de la Santé Et de la Recherche Médicale (INSERM), the University of Paris, the Laboratory of excellence GREx, the Bill and Melinda Gates Foundation (BMGF OPP1123683), and the « Sauver la Vie Foundation » (to PAB), the Wellcome Trust (Grant #099875 awarded to JRP and Senior Fellowship in Clinical Science awarded to RNP [#200909]), an Australian Government Postgraduate Award Scholarship and OzEMalaR Travel award (awarded to SK), a Royal Society Wolfson Research Merit award (awarded to MM), the Singapore National Medical Research Council (award to TWY [CSA INV 15nov007]), and the Australian Department of Foreign Affairs and Trade., We thank patients and relatives of patients in Indonesia and France for their participation and support, staff in the laboratory and operating theatre at RSUD hospital and French hospitals, Dr Daniel Lampah and Dr Freis Candrawati for clinical input, Dr Gregory Jouvion, Dr Sarah Auburn and Dr Jutta Marfurt for methodological and intellectual advice, Dr Grennady Wirjanata, Ms Aisah Resti Amelia and Mrs Magali Tichit for laboratory assistance, and Prof Yati Soenarto for facilitating the study. We are grateful to colleagues at the Timika Research Facility for their support., Hardy, David, Charles Darwin University-Charles Darwin University, Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), Institut Pasteur [Paris]-Université de Paris (UP), and University of Oxford [Oxford]

Subjects
Male, 0301 basic medicine, Plasmodium, Reticulocytes, Physiology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Plasmodium vivax, Medical Conditions, 0302 clinical medicine, Reticulocyte, Animal Cells, Immune Physiology, Red Blood Cells, Medicine and Health Sciences, Blood and Lymphatic System Procedures, Prospective Studies, Asymptomatic Infections, Protozoans, biology, Malarial Parasites, Eukaryota, General Medicine, Middle Aged, Body Fluids, 3. Good health, [SDV] Life Sciences [q-bio], Blood, medicine.anatomical_structure, Splenectomy, Red pulp, Medicine, Female, Cellular Types, Anatomy, medicine.symptom, Research Article, Adult, Adolescent, 030231 tropical medicine, Bone Marrow Cells, Surgical and Invasive Medical Procedures, Spleen, Asymptomatic, Young Adult, 03 medical and health sciences, Parasite Groups, parasitic diseases, Malaria, Vivax, Parasitic Diseases, medicine, Humans, New Guinea, Blood Cells, Organisms, Biology and Life Sciences, Plasmodium falciparum, Cell Biology, Tropical Diseases, biology.organism_classification, medicine.disease, Parasitic Protozoans, Malaria, 030104 developmental biology, Indonesia, Immunology, Parasitology, Apicomplexa
Abstract

Background A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival. Methods and findings We examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted. Conclusions Immature CD71+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen., Dr. Anstey and co-authors found that P. vivax-infected immature reticulocytes and erythrocytes accumulate in the same splenic compartments, suggesting existence of a cryptic endosplenic lifecycle in chronic P. vivax infection that maximizes survival and replication in the spleen., Author summary Why was this study done? There is a surprisingly large biomass of intact Plasmodium vivax parasites in the spleen of people living in malaria endemic areas, greater than with Plasmodium falciparum. Why P. vivax accumulates so intensely in the spleen is not known. P. vivax requires very young red cells (immature reticulocytes) for invasion and replication. What did the researchers do and find? The accumulation of P. vivax and immature reticulocytes were evaluated in spleens from people undergoing splenectomy in malaria-endemic Papua. P. vivax parasites and immature reticulocytes accumulated in the same splenic compartments. All stages of P. vivax accumulated in the spleen at magnitudes unexplainable by replication occurring in the circulation alone, with the proportion of each stage in the spleen consistent with the duration in their lifecycle. What do these findings mean? Taking advantage of the large physiological splenic reservoir of immature reticulocytes, the majority of the P. vivax lifecycle can take place in the spleen in chronic malaria. Chronic vivax malaria should be considered predominantly an infection of the reticulocyte-rich spleen, with secondary involvement of the intravascular compartment. The spleen is not solely a compartment for parasite destruction and clearance. Specific adaptations have likely evolved to maximise P. vivax survival in the spleen.

Published
2021

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