LeHavreV1, Main, Exploration, bibRecord, 000462

PftetQ and pfmdt copy numbers as predictive molecular markers of decreased ex vivo doxycycline susceptibility in imported Plasmodium falciparum malaria

Identifieur interne : 000462 ( Main/Exploration ); précédent : 000461; suivant : 000463

PftetQ and pfmdt copy numbers as predictive molecular markers of decreased ex vivo doxycycline susceptibility in imported Plasmodium falciparum malaria

Auteurs : Tiphaine Gaillard [France] ; Sébastien Briolant [France] ; Sandrine Houzé [France] ; Meïli Baragatti [France] ; Nathalie Wurtz [France] ; Véronique Hubert [France] ; Morgane Lavina [France] ; Aurélie Pascual [France] ; Christelle Travaillé [France] ; Jacques Le Bras [France] ; Bruno Pradines [France]

Source :

Malaria Journal [ 1475-2875 ] ; 2013.

RBID : PMC:3831056

Abstract

Background

The objective of this study was to evaluate the distribution of a series of independent doxycycline inhibitory concentration 50% (IC₅₀) values to validate the trimodal distribution previously described and to validate the use of the pftetQ and pfmdt genes as molecular markers of decreased in vitro doxycycline susceptibility in Plasmodium falciparum malaria.

Methods

Doxycycline IC₅₀ values, from 484 isolates obtained at the French National Reference Centre for Imported Malaria (Paris) between January 2006 and December 2010, were analysed for the first time by a Bayesian mixture modelling approach to distinguish the different in vitro phenotypic groups by their IC₅₀ values. Quantitative real-time polymerase chain reaction was used to evaluate the pftetQ and pfmdt copy numbers of 89 African P. falciparum isolates that were randomly chosen from the phenotypic groups.

Results

The existence of at least three doxycycline phenotypes was demonstrated. The mean doxycycline IC₅₀ was significantly higher in the group with a pftetQ copy number >1 compared to the group with a pftetQ copy number = 1 (33.17 μM versus 17.23 μM) and the group with a pfmdt copy number >1 (28.28 μM versus 16.11 μM). There was a significant difference between the combined low and medium doxycycline IC₅₀ group and the high IC₅₀ group in terms of the per cent of isolates with one or more copy numbers of the pftetQ gene (0% versus 20.69%) or pfmdt gene (8.33% versus 37.93%). In the logistic regression model, the pfmdt and pftetQ copy numbers >1 (odds ratio = 4.65 and 11.47) were independently associated with the high IC₅₀ group.

Conclusions

Copy numbers of pftetQ and pfmdt are potential predictive molecular markers of decreased susceptibility to doxycycline.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831056

DOI: 10.1186/1475-2875-12-414
PubMed: 24225377
PubMed Central: 3831056

Affiliations:

Le document en format XML

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<author><name sortKey="Houze, Sandrine" sort="Houze, Sandrine" uniqKey="Houze S" first="Sandrine" last="Houzé">Sandrine Houzé</name>
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<author><name sortKey="Baragatti, Meili" sort="Baragatti, Meili" uniqKey="Baragatti M" first="Meïli" last="Baragatti">Meïli Baragatti</name>
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<author><name sortKey="Wurtz, Nathalie" sort="Wurtz, Nathalie" uniqKey="Wurtz N" first="Nathalie" last="Wurtz">Nathalie Wurtz</name>
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<affiliation wicri:level="4"><nlm:aff id="I2">Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, Inserm 1095, Aix Marseille Université, Marseille, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, Inserm 1095, Aix Marseille Université, Marseille</wicri:regionArea>
<placeName><settlement type="city">Marseille</settlement>
</placeName>
<orgName type="university">Université d'Aix-Marseille</orgName>
<placeName><settlement type="city">Marseille</settlement>
<region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hubert, Veronique" sort="Hubert, Veronique" uniqKey="Hubert V" first="Véronique" last="Hubert">Véronique Hubert</name>
<affiliation wicri:level="1"><nlm:aff id="I4">Laboratoire de Parasitologie-Mycologie, Hôpital Bichat-Claude Bernard, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Laboratoire de Parasitologie-Mycologie, Hôpital Bichat-Claude Bernard, Paris</wicri:regionArea>
<placeName><settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="I6">Centre National de Référence du Paludisme, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Centre National de Référence du Paludisme, Paris</wicri:regionArea>
<placeName><settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lavina, Morgane" sort="Lavina, Morgane" uniqKey="Lavina M" first="Morgane" last="Lavina">Morgane Lavina</name>
<affiliation wicri:level="1"><nlm:aff id="I1">Unité de Parasitologie, Institut de Recherche Biomédicale des Armées, Marseille, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Unité de Parasitologie, Institut de Recherche Biomédicale des Armées, Marseille</wicri:regionArea>
<placeName><settlement type="city">Marseille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="I2">Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, Inserm 1095, Aix Marseille Université, Marseille, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, Inserm 1095, Aix Marseille Université, Marseille</wicri:regionArea>
<placeName><settlement type="city">Marseille</settlement>
</placeName>
<orgName type="university">Université d'Aix-Marseille</orgName>
<placeName><settlement type="city">Marseille</settlement>
<region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pascual, Aurelie" sort="Pascual, Aurelie" uniqKey="Pascual A" first="Aurélie" last="Pascual">Aurélie Pascual</name>
<affiliation wicri:level="1"><nlm:aff id="I1">Unité de Parasitologie, Institut de Recherche Biomédicale des Armées, Marseille, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Unité de Parasitologie, Institut de Recherche Biomédicale des Armées, Marseille</wicri:regionArea>
<placeName><settlement type="city">Marseille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="I2">Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, Inserm 1095, Aix Marseille Université, Marseille, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, Inserm 1095, Aix Marseille Université, Marseille</wicri:regionArea>
<placeName><settlement type="city">Marseille</settlement>
</placeName>
<orgName type="university">Université d'Aix-Marseille</orgName>
<placeName><settlement type="city">Marseille</settlement>
<region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region>
</placeName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="I6">Centre National de Référence du Paludisme, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Centre National de Référence du Paludisme, Paris</wicri:regionArea>
<placeName><settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Travaille, Christelle" sort="Travaille, Christelle" uniqKey="Travaille C" first="Christelle" last="Travaillé">Christelle Travaillé</name>
<affiliation wicri:level="1"><nlm:aff id="I8">Unité de Recherche Mixte MD3, Institut de Recherche Biomédicale des Armées, Marseille, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Unité de Recherche Mixte MD3, Institut de Recherche Biomédicale des Armées, Marseille</wicri:regionArea>
<placeName><settlement type="city">Marseille</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Le Bras, Jacques" sort="Le Bras, Jacques" uniqKey="Le Bras J" first="Jacques" last="Le Bras">Jacques Le Bras</name>
<affiliation wicri:level="1"><nlm:aff id="I4">Laboratoire de Parasitologie-Mycologie, Hôpital Bichat-Claude Bernard, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Laboratoire de Parasitologie-Mycologie, Hôpital Bichat-Claude Bernard, Paris</wicri:regionArea>
<placeName><settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="I5">Unité Mixte de Recherche 216 IRD, Université Paris Descartes, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Unité Mixte de Recherche 216 IRD, Université Paris Descartes, Paris</wicri:regionArea>
<placeName><settlement type="city">Paris</settlement>
</placeName>
<orgName type="university">Université Paris Descartes</orgName>
<placeName><settlement type="city">Paris</settlement>
<region type="region" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="I6">Centre National de Référence du Paludisme, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Centre National de Référence du Paludisme, Paris</wicri:regionArea>
<placeName><settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pradines, Bruno" sort="Pradines, Bruno" uniqKey="Pradines B" first="Bruno" last="Pradines">Bruno Pradines</name>
<affiliation wicri:level="1"><nlm:aff id="I1">Unité de Parasitologie, Institut de Recherche Biomédicale des Armées, Marseille, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Unité de Parasitologie, Institut de Recherche Biomédicale des Armées, Marseille</wicri:regionArea>
<placeName><settlement type="city">Marseille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="I2">Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, Inserm 1095, Aix Marseille Université, Marseille, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, Inserm 1095, Aix Marseille Université, Marseille</wicri:regionArea>
<placeName><settlement type="city">Marseille</settlement>
</placeName>
<orgName type="university">Université d'Aix-Marseille</orgName>
<placeName><settlement type="city">Marseille</settlement>
<region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region>
</placeName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="I6">Centre National de Référence du Paludisme, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Centre National de Référence du Paludisme, Paris</wicri:regionArea>
<placeName><settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Malaria Journal</title>
<idno type="eISSN">1475-2875</idno>
<imprint><date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>The objective of this study was to evaluate the distribution of a series of independent doxycycline inhibitory concentration 50% (IC<sub>50</sub>
) values to validate the trimodal distribution previously described and to validate the use of the <italic>pftetQ</italic>
 and <italic>pfmdt</italic>
 genes as molecular markers of decreased <italic>in vitro</italic>
 doxycycline susceptibility in <italic>Plasmodium falciparum</italic>
 malaria.</p>
</sec>
<sec><title>Methods</title>
<p>Doxycycline IC<sub>50</sub>
 values, from 484 isolates obtained at the French National Reference Centre for Imported Malaria (Paris) between January 2006 and December 2010, were analysed for the first time by a Bayesian mixture modelling approach to distinguish the different <italic>in vitro</italic>
 phenotypic groups by their IC<sub>50</sub>
 values. Quantitative real-time polymerase chain reaction was used to evaluate the <italic>pftetQ</italic>
 and <italic>pfmdt</italic>
 copy numbers of 89 African <italic>P. falciparum</italic>
 isolates that were randomly chosen from the phenotypic groups.</p>
</sec>
<sec><title>Results</title>
<p>The existence of at least three doxycycline phenotypes was demonstrated. The mean doxycycline IC<sub>50</sub>
 was significantly higher in the group with a <italic>pftetQ</italic>
 copy number >1 compared to the group with a <italic>pftetQ</italic>
 copy number = 1 (33.17 μM <italic>versus</italic>
 17.23 μM) and the group with a <italic>pfmdt</italic>
 copy number >1 (28.28 μM <italic>versus</italic>
 16.11 μM). There was a significant difference between the combined low and medium doxycycline IC<sub>50</sub>
 group and the high IC<sub>50</sub>
 group in terms of the per cent of isolates with one or more copy numbers of the <italic>pftetQ</italic>
 gene (0% <italic>versus</italic>
 20.69%) or <italic>pfmdt</italic>
 gene (8.33% <italic>versus</italic>
 37.93%). In the logistic regression model, the <italic>pfmdt</italic>
 and <italic>pftetQ</italic>
 copy numbers >1 (odds ratio = 4.65 and 11.47) were independently associated with the high IC<sub>50</sub>
 group.</p>
</sec>
<sec><title>Conclusions</title>
<p>Copy numbers of <italic>pftetQ</italic>
 and <italic>pfmdt</italic>
 are potential predictive molecular markers of decreased susceptibility to doxycycline.</p>
</sec>
</div>
</front>
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<author><name sortKey="Briolant, S" uniqKey="Briolant S">S Briolant</name>
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<settlement><li>Marseille</li>
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PftetQ and pfmdt copy numbers as predictive molecular markers of decreased ex vivo doxycycline susceptibility in imported Plasmodium falciparum malaria

PftetQ and pfmdt copy numbers as predictive molecular markers of decreased ex vivo doxycycline susceptibility in imported Plasmodium falciparum malaria

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