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      Sulfadiazine resistance in Toxoplasma gondii: no involvement of overexpression or polymorphisms in genes of therapeutic targets and ABC transporters Translated title: Résistance à la sulfadiazine chez Toxoplasma gondii : pas de participation de surexpression ni de polymorphismes dans les gènes des cibles thérapeutiques et des ABC transporteurs

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          Abstract

          Several treatment failures have been reported for the treatment of toxoplasmic encephalitis, chorioretinitis, and congenital toxoplasmosis. Recently we found three Toxoplasma gondii strains naturally resistant to sulfadiazine and we developed in vitro two sulfadiazine resistant strains, RH-R SDZ and ME-49-R SDZ, by gradual pressure. In Plasmodium, common mechanisms of drug resistance involve, among others, mutations and/or amplification within genes encoding the therapeutic targets dhps and dhfr and/or the ABC transporter genes family. To identify genotypic and/or phenotypic markers of resistance in T. gondii, we sequenced and analyzed the expression levels of therapeutic targets dhps and dhfr, three ABC genes, two Pgp, TgABC.B1 and TgABC.B2, and one MRP, TgABC.C1, on sensitive strains compared to sulfadiazine resistant strains. Neither polymorphism nor overexpression was identified. Contrary to Plasmodium, in which mutations and/or overexpression within gene targets and ABC transporters are involved in antimalarial resistance, T. gondii sulfadiazine resistance is not related to these toxoplasmic genes studied.

          Translated abstract

          De nombreux échecs thérapeutiques ont été rapportés dans le traitement de la toxoplasmose cérébrale, des choriorétinites et de la toxoplasmose congénitale. Récemment, nous avons identifié trois souches de Toxoplasma gondii naturellement résistantes à la sulfadiazine et nous avons développé in vitro, par pression médicamenteuse croissante, deux souches résistantes à la sulfadiazine, RH-R SDZ et ME-49-R SDZ. Chez Plasmodium, les mécanismes de résistance impliquent, entre autres, la mutation et/ou l’amplification de gènes codant pour les cibles thérapeutiques, dhps et dhfr, et/ou les gènes de la famille des ABC transporteurs. Afin d’identifier des marqueurs génotypiques et/ou phénotypiques de résistance de T. gondii, nous avons séquencé et analysé les niveaux d’expression des gènes cibles, dhps, dhfr, et de trois gènes de transporteurs ABC, deux Pgp, TgABC.B1 et TgABC.B2, et une MRP, TgABC.C1, par comparaison des souches sensibles et résistantes à la sulfadiazine. Aucun polymorphisme ni surexpression de gènes n’ont été identifiés. Contrairement à Plasmodium, dont les mutations et/ou surexpressions des gènes cibles et ABC transporteurs sont impliquées dans la résistance aux antipaludiques, les mécanismes de résistance à la sulfadiazine chez T. gondii ne sont pas liés à ces gènes toxoplasmiques étudiés.

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          Most cited references 15

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          Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number.

          The borders of Thailand harbour the world's most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known. The relation between polymorphisms in the P falciparum multidrug resistant gene 1 (pfmdr1) and the in-vitro and in-vivo responses to mefloquine were assessed in 618 samples from patients with falciparum malaria studied prospectively over 12 years. pfmdr1 copy number was assessed by a robust real-time PCR assay. Single nucleotide polymorphisms of pfmdr1, P falciparum chloroquine resistance transporter gene (pfcrt) and P falciparum Ca2+ ATPase gene (pfATP6) were assessed by PCR-restriction fragment length polymorphism. Increased copy number of pfmdr1 was the most important determinant of in-vitro and in-vivo resistance to mefloquine, and also to reduced artesunate sensitivity in vitro. In a Cox regression model with control for known confounders, increased pfmdr1 copy number was associated with an attributable hazard ratio (AHR) for treatment failure of 6.3 (95% CI 2.9-13.8, p<0.001) after mefloquine monotherapy and 5.4 (2.0-14.6, p=0.001) after artesunate-mefloquine therapy. Single nucleotide polymorphisms in pfmdr1 were associated with increased mefloquine susceptibility in vitro, but not in vivo. Amplification in pfmdr1 is the main cause of resistance to mefloquine in falciparum malaria. Multidrug resistant P falciparum malaria is common in southeast Asia, but difficult to identify and treat. Genes that encode parasite transport proteins maybe involved in export of drugs and so cause resistance. In this study we show that increase in copy number of pfmdr1, a gene encoding a parasite transport protein, is the best overall predictor of treatment failure with mefloquine. Increase in pfmdr1 copy number predicts failure even after chemotherapy with the highly effective combination of mefloquine and 3 days' artesunate. Monitoring of pfmdr1 copy number will be useful in epidemiological surveys of drug resistance in P falciparum, and potentially for predicting treatment failure in individual patients.
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            Toxoplasmosis: A history of clinical observations.

            It has been 100 years since Toxoplasma gondii was initially described in Tunis by Nicolle and Manceaux (1908) in the tissues of the gundi (Ctenodoactylus gundi) and in Brazil by Splendore (1908) in the tissues of a rabbit. Toxoplasma gondii is a ubiquitous, Apicomplexan parasite of warm-blooded animals that can cause several clinical syndromes including encephalitis, chorioretinitis, congenital infection and neonatal mortality. Fifteen years after the description of T. gondii by Nicolle and Manceaux a fatal case of toxoplasmosis in a child was reported by Janků. In 1939 Wolf, Cowen and Paige were the first to conclusively identify T. gondii as a cause of human disease. This review examines the clinical manifestations of infection with T. gondii and the history of the discovery of these manifestations.
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              Toxoplasma gondii comprises three clonal lineages: correlation of parasite genotype with human disease.

               Laura Howe,  L. Sibley (1995)
              The population genetic structure of Toxoplasma gondii was determined by multilocus restriction fragment length polymorphism analysis at 6 loci in 106 independent isolates from humans and animals. Phylogenetic and statistical analyses indicated a highly unusual population structure consisting of 3 widespread clonal lineages. Extensively mixed genotypes were only apparent in 4 strains, which indicated that, while not separate species, sexual recombination between the 3 lineages is exceedingly rare in natural populations. T. gondii is a major cause of subclinical human infection and an important opportunistic pathogen that causes severe disease in immunocompromised patients. While strains from all 3 lineages were isolated from humans, the majority of human toxoplasmosis cases were associated with strains of a type II genotype. The correlation of specific clonal lineages with human toxoplasmosis has important implications for development of vaccines, drug treatments, and diagnostic protocols.
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                Author and article information

                Journal
                Parasite
                Parasite
                parasite
                Parasite
                EDP Sciences
                1252-607X
                1776-1042
                2013
                27 May 2013
                : 20
                : ( publisher-idID: parasite/2013/01 )
                Affiliations
                [1 ] Laboratoire de Parasitologie-Mycologie, EA 3800, SFR CAP-Santé FED 4231, UFR Médecine, Université de Reims Champagne-Ardenne 51 rue Cognacq-Jay 51095 Reims Cedex France
                [2 ] CRB Toxoplasma et CNR de la Toxoplasmose, Hôpital Maison Blanche 45 rue Cognacq- Jay 51092 Reims Cedex France
                [3 ] Plateforme d’Imagerie Cellulaire et Tissulaire 51 rue Cognacq-Jay 51096 Reims Cedex France
                [4 ] EA 4691 BIOS : Biomatériaux et inflammation en site osseux, SFR CAP-Santé FED 4231, Université de Reims Champagne-Ardenne 51 rue Cognacq-Jay 51095 Reims Cedex France
                Author notes
                [a]

                These authors contribute equally to this work.

                [* ]Corresponding author: ivillena@ 123456chu-reims.fr
                Article
                parasite130006 10.1051/parasite/2013020
                10.1051/parasite/2013020
                3718540
                23707894
                © C. Doliwa et al., published by EDP Sciences, 2013

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 17, Pages: 6
                Categories
                Research Article

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