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Splenic Retention of Plasmodium falciparum Gametocytes To Block the Transmission of Malaria

Identifieur interne : 002815 ( Main/Exploration ); précédent : 002814; suivant : 002816

Splenic Retention of Plasmodium falciparum Gametocytes To Block the Transmission of Malaria

Auteurs : Julien Duez [France, Australie] ; John P. Holleran [Australie] ; Papa Alioune Ndour [France] ; Sasdekumar Loganathan [Australie] ; Pascal Amireault [France] ; Olivier Français [France] ; Wassim El Nemer [France] ; Bruno Le Pioufle [France] ; Inês F. Amado [France] ; Sylvie Garcia [France] ; Nathalie Chartrel [France] ; Caroline Le Van Kim [France] ; Catherine Lavazec [France] ; Vicky M. Avery [Australie] ; Pierre A. Buffet [France]

Source :

RBID : PMC:4468678

Descripteurs français

English descriptors

Abstract

Plasmodium falciparum is transmitted from humans to Anopheles mosquito vectors via the sexual erythrocytic forms termed gametocytes. Erythrocyte filtration through microsphere layers (microsphiltration) had shown that circulating gametocytes are deformable. Compounds reducing gametocyte deformability would induce their splenic clearance, thus removing them from the blood circulation and blocking malaria transmission. The hand-made, single-sample prototype for microsphiltration was miniaturized to a 96-well microtiter plate format, and gametocyte retention in the microsphere filters was quantified by high-content imaging. The stiffening activity of 40 pharmacological compounds was assessed in microtiter plates, using a small molecule (calyculin) as a positive control. The stiffening activity of calyculin was assessed in spleen-mimetic microfluidic chips and in macrophage-depleted mice. Marked mechanical retention (80% to 90%) of mature gametocytes was obtained in microplates following exposure to calyculin at concentrations with no effect on parasite viability. Of the 40 compounds tested, including 20 antimalarials, only 5 endoperoxides significantly increased gametocyte retention (1.5- to 2.5-fold; 24 h of exposure at 1 μM). Mature gametocytes exposed to calyculin accumulated in microfluidic chips and were cleared from the circulation of macrophage-depleted mice as rapidly as heat-stiffened erythrocytes, thus confirming results obtained using the microsphiltration assay. An automated miniaturized approach to select compounds for their gametocyte-stiffening effect has been established. Stiffening induces gametocyte clearance both in vitro and in vivo. Based on physiologically validated tools, this screening cascade can identify novel compounds and uncover new targets to block malaria transmission. Innovative applications in hematology are also envisioned.


Url:
DOI: 10.1128/AAC.05030-14
PubMed: 25941228
PubMed Central: 4468678


Affiliations:


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Le document en format XML

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<name sortKey="Francais, Olivier" sort="Francais, Olivier" uniqKey="Francais O" first="Olivier" last="Français">Olivier Français</name>
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<name sortKey="Garcia, Sylvie" sort="Garcia, Sylvie" uniqKey="Garcia S" first="Sylvie" last="Garcia">Sylvie Garcia</name>
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<name sortKey="Chartrel, Nathalie" sort="Chartrel, Nathalie" uniqKey="Chartrel N" first="Nathalie" last="Chartrel">Nathalie Chartrel</name>
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<name sortKey="Le Van Kim, Caroline" sort="Le Van Kim, Caroline" uniqKey="Le Van Kim C" first="Caroline" last="Le Van Kim">Caroline Le Van Kim</name>
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<name sortKey="Lavazec, Catherine" sort="Lavazec, Catherine" uniqKey="Lavazec C" first="Catherine" last="Lavazec">Catherine Lavazec</name>
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<name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M." last="Avery">Vicky M. Avery</name>
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<title xml:lang="en" level="a" type="main">Splenic Retention of
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Gametocytes To Block the Transmission of Malaria</title>
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<name sortKey="Ndour, Papa Alioune" sort="Ndour, Papa Alioune" uniqKey="Ndour P" first="Papa Alioune" last="Ndour">Papa Alioune Ndour</name>
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<name sortKey="Loganathan, Sasdekumar" sort="Loganathan, Sasdekumar" uniqKey="Loganathan S" first="Sasdekumar" last="Loganathan">Sasdekumar Loganathan</name>
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<name sortKey="Amireault, Pascal" sort="Amireault, Pascal" uniqKey="Amireault P" first="Pascal" last="Amireault">Pascal Amireault</name>
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<nlm:aff id="aff3">INSERM U1163/CNRS ERL 8254, Institut Imagine, Paris Descartes—Université Sorbonne Paris Cité, Paris, France</nlm:aff>
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<nlm:aff id="aff4">Laboratoire d'Excellence GR-Ex, Paris, France</nlm:aff>
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<region type="region">Île-de-France</region>
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<nlm:aff id="aff5">Institut National de la Transfusion Sanguine (INTS), Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
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<name sortKey="Francais, Olivier" sort="Francais, Olivier" uniqKey="Francais O" first="Olivier" last="Français">Olivier Français</name>
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<nlm:aff id="aff6">Ecole Normale Supérieure de Cachan, CNRS, BIOMIS-SATIE, UMR 8029, Cachan, France</nlm:aff>
<country xml:lang="fr">France</country>
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<author>
<name sortKey="El Nemer, Wassim" sort="El Nemer, Wassim" uniqKey="El Nemer W" first="Wassim" last="El Nemer">Wassim El Nemer</name>
<affiliation wicri:level="3">
<nlm:aff id="aff5">Institut National de la Transfusion Sanguine (INTS), Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut National de la Transfusion Sanguine (INTS), Paris</wicri:regionArea>
<placeName>
<region type="region">Île-de-France</region>
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<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Le Pioufle, Bruno" sort="Le Pioufle, Bruno" uniqKey="Le Pioufle B" first="Bruno" last="Le Pioufle">Bruno Le Pioufle</name>
<affiliation wicri:level="1">
<nlm:aff id="aff6">Ecole Normale Supérieure de Cachan, CNRS, BIOMIS-SATIE, UMR 8029, Cachan, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Ecole Normale Supérieure de Cachan, CNRS, BIOMIS-SATIE, UMR 8029, Cachan</wicri:regionArea>
<wicri:noRegion>Cachan</wicri:noRegion>
<wicri:noRegion>Cachan</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Amado, Ines F" sort="Amado, Ines F" uniqKey="Amado I" first="Inês F." last="Amado">Inês F. Amado</name>
<affiliation wicri:level="3">
<nlm:aff id="aff7">Institut Pasteur de Paris, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut Pasteur de Paris, Paris</wicri:regionArea>
<placeName>
<region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Garcia, Sylvie" sort="Garcia, Sylvie" uniqKey="Garcia S" first="Sylvie" last="Garcia">Sylvie Garcia</name>
<affiliation wicri:level="3">
<nlm:aff id="aff7">Institut Pasteur de Paris, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut Pasteur de Paris, Paris</wicri:regionArea>
<placeName>
<region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Chartrel, Nathalie" sort="Chartrel, Nathalie" uniqKey="Chartrel N" first="Nathalie" last="Chartrel">Nathalie Chartrel</name>
<affiliation wicri:level="3">
<nlm:aff id="aff1">Centre d'Immunologie et des Maladies Infectieuses de Paris (CIMI-Paris), INSERM U1135, UPMC CR7, CNRS ERL 8255, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Centre d'Immunologie et des Maladies Infectieuses de Paris (CIMI-Paris), INSERM U1135, UPMC CR7, CNRS ERL 8255, Paris</wicri:regionArea>
<placeName>
<region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Le Van Kim, Caroline" sort="Le Van Kim, Caroline" uniqKey="Le Van Kim C" first="Caroline" last="Le Van Kim">Caroline Le Van Kim</name>
<affiliation wicri:level="3">
<nlm:aff id="aff5">Institut National de la Transfusion Sanguine (INTS), Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut National de la Transfusion Sanguine (INTS), Paris</wicri:regionArea>
<placeName>
<region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Lavazec, Catherine" sort="Lavazec, Catherine" uniqKey="Lavazec C" first="Catherine" last="Lavazec">Catherine Lavazec</name>
<affiliation wicri:level="3">
<nlm:aff id="aff7">Institut Pasteur de Paris, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut Pasteur de Paris, Paris</wicri:regionArea>
<placeName>
<region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M." last="Avery">Vicky M. Avery</name>
<affiliation wicri:level="1">
<nlm:aff id="aff2">Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD</wicri:regionArea>
<wicri:noRegion>QLD</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Buffet, Pierre A" sort="Buffet, Pierre A" uniqKey="Buffet P" first="Pierre A." last="Buffet">Pierre A. Buffet</name>
<affiliation wicri:level="3">
<nlm:aff id="aff1">Centre d'Immunologie et des Maladies Infectieuses de Paris (CIMI-Paris), INSERM U1135, UPMC CR7, CNRS ERL 8255, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Centre d'Immunologie et des Maladies Infectieuses de Paris (CIMI-Paris), INSERM U1135, UPMC CR7, CNRS ERL 8255, Paris</wicri:regionArea>
<placeName>
<region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3">
<nlm:aff id="aff4">Laboratoire d'Excellence GR-Ex, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Laboratoire d'Excellence GR-Ex, Paris</wicri:regionArea>
<placeName>
<region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Antimicrobial Agents and Chemotherapy</title>
<idno type="ISSN">0066-4804</idno>
<idno type="eISSN">1098-6596</idno>
<imprint>
<date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass>
<keywords scheme="KwdEn" xml:lang="en">
<term>Animals</term>
<term>Antimalarials (pharmacology)</term>
<term>Automation</term>
<term>Enzyme Inhibitors (pharmacology)</term>
<term>Erythrocyte Count</term>
<term>Erythrocytes (parasitology)</term>
<term>Filtration</term>
<term>Flow Cytometry</term>
<term>Image Processing, Computer-Assisted</term>
<term>Macrophages (parasitology)</term>
<term>Malaria, Falciparum (parasitology)</term>
<term>Malaria, Falciparum (prevention & control)</term>
<term>Malaria, Falciparum (transmission)</term>
<term>Mice</term>
<term>Microfluidic Analytical Techniques</term>
<term>Microspheres</term>
<term>Models, Biological</term>
<term>Oxazoles (pharmacology)</term>
<term>Parasite Egg Count</term>
<term>Plasmodium falciparum (growth & development)</term>
<term>Spleen (drug effects)</term>
<term>Spleen (parasitology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Animaux</term>
<term>Antienzymes (pharmacologie)</term>
<term>Antipaludiques (pharmacologie)</term>
<term>Automatisation</term>
<term>Cytométrie en flux</term>
<term>Filtration</term>
<term>Macrophages (parasitologie)</term>
<term>Microsphères</term>
<term>Modèles biologiques</term>
<term>Numération des oeufs de parasites</term>
<term>Numération des érythrocytes</term>
<term>Oxazoles (pharmacologie)</term>
<term>Paludisme à Plasmodium falciparum ()</term>
<term>Paludisme à Plasmodium falciparum (parasitologie)</term>
<term>Paludisme à Plasmodium falciparum (transmission)</term>
<term>Plasmodium falciparum (croissance et développement)</term>
<term>Rate ()</term>
<term>Rate (parasitologie)</term>
<term>Souris</term>
<term>Techniques d'analyse microfluidique</term>
<term>Traitement d'image par ordinateur</term>
<term>Érythrocytes (parasitologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en">
<term>Antimalarials</term>
<term>Enzyme Inhibitors</term>
<term>Oxazoles</term>
</keywords>
<keywords scheme="MESH" qualifier="croissance et développement" xml:lang="fr">
<term>Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en">
<term>Spleen</term>
</keywords>
<keywords scheme="MESH" qualifier="growth & development" xml:lang="en">
<term>Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="parasitologie" xml:lang="fr">
<term>Macrophages</term>
<term>Paludisme à Plasmodium falciparum</term>
<term>Rate</term>
<term>Érythrocytes</term>
</keywords>
<keywords scheme="MESH" qualifier="parasitology" xml:lang="en">
<term>Erythrocytes</term>
<term>Macrophages</term>
<term>Malaria, Falciparum</term>
<term>Spleen</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr">
<term>Antienzymes</term>
<term>Antipaludiques</term>
<term>Oxazoles</term>
</keywords>
<keywords scheme="MESH" qualifier="prevention & control" xml:lang="en">
<term>Malaria, Falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="transmission" xml:lang="en">
<term>Malaria, Falciparum</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Animals</term>
<term>Automation</term>
<term>Erythrocyte Count</term>
<term>Filtration</term>
<term>Flow Cytometry</term>
<term>Image Processing, Computer-Assisted</term>
<term>Mice</term>
<term>Microfluidic Analytical Techniques</term>
<term>Microspheres</term>
<term>Models, Biological</term>
<term>Parasite Egg Count</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Animaux</term>
<term>Automatisation</term>
<term>Cytométrie en flux</term>
<term>Filtration</term>
<term>Microsphères</term>
<term>Modèles biologiques</term>
<term>Numération des oeufs de parasites</term>
<term>Numération des érythrocytes</term>
<term>Paludisme à Plasmodium falciparum</term>
<term>Rate</term>
<term>Souris</term>
<term>Techniques d'analyse microfluidique</term>
<term>Traitement d'image par ordinateur</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p>
<named-content content-type="genus-species">Plasmodium falciparum</named-content>
is transmitted from humans to
<named-content content-type="genus-species">Anopheles</named-content>
mosquito vectors via the sexual erythrocytic forms termed gametocytes. Erythrocyte filtration through microsphere layers (microsphiltration) had shown that circulating gametocytes are deformable. Compounds reducing gametocyte deformability would induce their splenic clearance, thus removing them from the blood circulation and blocking malaria transmission. The hand-made, single-sample prototype for microsphiltration was miniaturized to a 96-well microtiter plate format, and gametocyte retention in the microsphere filters was quantified by high-content imaging. The stiffening activity of 40 pharmacological compounds was assessed in microtiter plates, using a small molecule (calyculin) as a positive control. The stiffening activity of calyculin was assessed in spleen-mimetic microfluidic chips and in macrophage-depleted mice. Marked mechanical retention (80% to 90%) of mature gametocytes was obtained in microplates following exposure to calyculin at concentrations with no effect on parasite viability. Of the 40 compounds tested, including 20 antimalarials, only 5 endoperoxides significantly increased gametocyte retention (1.5- to 2.5-fold; 24 h of exposure at 1 μM). Mature gametocytes exposed to calyculin accumulated in microfluidic chips and were cleared from the circulation of macrophage-depleted mice as rapidly as heat-stiffened erythrocytes, thus confirming results obtained using the microsphiltration assay. An automated miniaturized approach to select compounds for their gametocyte-stiffening effect has been established. Stiffening induces gametocyte clearance both
<italic>in vitro</italic>
and
<italic>in vivo</italic>
. Based on physiologically validated tools, this screening cascade can identify novel compounds and uncover new targets to block malaria transmission. Innovative applications in hematology are also envisioned.</p>
</div>
</front>
</TEI>
<affiliations>
<list>
<country>
<li>Australie</li>
<li>France</li>
</country>
<region>
<li>Île-de-France</li>
</region>
<settlement>
<li>Paris</li>
</settlement>
</list>
<tree>
<country name="France">
<region name="Île-de-France">
<name sortKey="Duez, Julien" sort="Duez, Julien" uniqKey="Duez J" first="Julien" last="Duez">Julien Duez</name>
</region>
<name sortKey="Amado, Ines F" sort="Amado, Ines F" uniqKey="Amado I" first="Inês F." last="Amado">Inês F. Amado</name>
<name sortKey="Amireault, Pascal" sort="Amireault, Pascal" uniqKey="Amireault P" first="Pascal" last="Amireault">Pascal Amireault</name>
<name sortKey="Amireault, Pascal" sort="Amireault, Pascal" uniqKey="Amireault P" first="Pascal" last="Amireault">Pascal Amireault</name>
<name sortKey="Amireault, Pascal" sort="Amireault, Pascal" uniqKey="Amireault P" first="Pascal" last="Amireault">Pascal Amireault</name>
<name sortKey="Buffet, Pierre A" sort="Buffet, Pierre A" uniqKey="Buffet P" first="Pierre A." last="Buffet">Pierre A. Buffet</name>
<name sortKey="Buffet, Pierre A" sort="Buffet, Pierre A" uniqKey="Buffet P" first="Pierre A." last="Buffet">Pierre A. Buffet</name>
<name sortKey="Chartrel, Nathalie" sort="Chartrel, Nathalie" uniqKey="Chartrel N" first="Nathalie" last="Chartrel">Nathalie Chartrel</name>
<name sortKey="Duez, Julien" sort="Duez, Julien" uniqKey="Duez J" first="Julien" last="Duez">Julien Duez</name>
<name sortKey="El Nemer, Wassim" sort="El Nemer, Wassim" uniqKey="El Nemer W" first="Wassim" last="El Nemer">Wassim El Nemer</name>
<name sortKey="Francais, Olivier" sort="Francais, Olivier" uniqKey="Francais O" first="Olivier" last="Français">Olivier Français</name>
<name sortKey="Garcia, Sylvie" sort="Garcia, Sylvie" uniqKey="Garcia S" first="Sylvie" last="Garcia">Sylvie Garcia</name>
<name sortKey="Lavazec, Catherine" sort="Lavazec, Catherine" uniqKey="Lavazec C" first="Catherine" last="Lavazec">Catherine Lavazec</name>
<name sortKey="Le Pioufle, Bruno" sort="Le Pioufle, Bruno" uniqKey="Le Pioufle B" first="Bruno" last="Le Pioufle">Bruno Le Pioufle</name>
<name sortKey="Le Van Kim, Caroline" sort="Le Van Kim, Caroline" uniqKey="Le Van Kim C" first="Caroline" last="Le Van Kim">Caroline Le Van Kim</name>
<name sortKey="Ndour, Papa Alioune" sort="Ndour, Papa Alioune" uniqKey="Ndour P" first="Papa Alioune" last="Ndour">Papa Alioune Ndour</name>
<name sortKey="Ndour, Papa Alioune" sort="Ndour, Papa Alioune" uniqKey="Ndour P" first="Papa Alioune" last="Ndour">Papa Alioune Ndour</name>
</country>
<country name="Australie">
<noRegion>
<name sortKey="Duez, Julien" sort="Duez, Julien" uniqKey="Duez J" first="Julien" last="Duez">Julien Duez</name>
</noRegion>
<name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M." last="Avery">Vicky M. Avery</name>
<name sortKey="Holleran, John P" sort="Holleran, John P" uniqKey="Holleran J" first="John P." last="Holleran">John P. Holleran</name>
<name sortKey="Loganathan, Sasdekumar" sort="Loganathan, Sasdekumar" uniqKey="Loganathan S" first="Sasdekumar" last="Loganathan">Sasdekumar Loganathan</name>
</country>
</tree>
</affiliations>
</record>

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