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      Genetic Polymorphisms and Phenotypic Profiles of Sulfadiazine-Resistant and Sensitive Toxoplasma gondii Isolates Obtained from Newborns with Congenital Toxoplasmosis in Minas Gerais, Brazil

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          Abstract

          Background

          Previous Toxoplasma gondii studies revealed that mutations in the dhps ( dihydropteroate synthase) gene are associated with resistance to sulfonamides. Although Brazilian strains are genotypically different, very limited data are available regarding the susceptibility of strains obtained from human to sulfonamides. The aim of this study was to evaluate the efficacy of sulfadiazine (SDZ) against Brazilian isolates of T. gondii and verify whether isolates present polymorphisms in the dhps gene. We also investigated whether the virulence-phenotype and/or genotype were associated with the profile of susceptibility to SDZ.

          Methods

          Five T. gondii isolates obtained from newborns with congenital toxoplasmosis were used to verify susceptibility. Mice were infected with 10 4 tachyzoites and orally treated with different doses of SDZ. The mortality curve was evaluated by the Log-rank test. The presence of polymorphisms in the dhps gene was verified using sequencing. A descriptive analysis for 11 Brazilian isolates was used to assess the association between susceptibility, genotype, and virulence-phenotype.

          Results

          Statistical analysis showed that TgCTBr03, 07, 08, and 16 isolates were susceptible to SDZ, whereas TgCTBr11 isolate presented a profile of resistance to SDZ. Nineteen polymorphisms were identified in dhps exons. Seven polymorphisms corresponded to non-synonymous mutations, with four being new mutations, described for the first time in this study. No association was found between the profile of susceptibility and the virulence-phenotype or genotype of the parasite.

          Conclusions

          There is a high variability in the susceptibilities of Brazilian T. gondii strains to SDZ, with evidence of drug resistance. Despite the large number of polymorphisms identified, the profile of susceptibility to SDZ was not associated with any of the dhps variants identified in this study. Other genetic factors, not yet determined, may be associated with the resistance to SDZ; thus, further studies are needed as a basis for a more adequate toxoplasmosis treatment.

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          Most cited references20

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          Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum.

          F B J Menting, Chris C. Wilson, A. Cowman … (1997)
          Plasmodium falciparum causes the most severe form of malaria in humans. An important class of drugs in malaria treatment is the sulfone/sulfonamide group, of which sulfadoxine is the most commonly used. The target of sulfadoxine is the enzyme dihydropteroate synthase (DHPS), and sequencing of the DHPS gene has identified amino acid differences that may be involved in the mechanism of resistance to this drug. In this study we have sequenced the DHPS gene in 10 isolates from Thailand and identified a new allele of DHPS that has a previously unidentified amino acid difference. We have expressed eight alleles of P. falciparum PPPK-DHPS in Escherichia coli and purified the functional enzymes to homogeneity. Strikingly, the Ki for sulfadoxine varies by almost three orders of magnitude from 0.14 microM for the DHPS allele from sensitive isolates to 112 microM for an enzyme expressed in a highly resistant isolate. Comparison of the Ki of different sulfonamides and the sulfone dapsone has suggested that the amino acid differences in DHPS would confer cross-resistance to these compounds. These results show that the amino acid differences in the DHPS enzyme of sulfadoxine-resistant isolates of P. falciparum are central to the mechanism of resistance to sulfones and sulfonamides.
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            Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization.

            Steve M. Read, Gary P. Sims, P. Wang … (1997)
            Sulfadoxine/pyrimethamine (Fansidar) is widely used in Africa for treating chloroquine-resistant falciparum malaria. To clarify how parasite resistance to this combination arises, various lines of Plasmodium falciparum were used to investigate the role of naturally occurring mutations in the target enzyme, dihydropteroate synthetase (DHPS), in the parasite response to sulfadoxine inhibition. An improved drug assay was employed to identify a clear correlation between sulfadoxine-resistance levels and the number of DHPS mutations. Moreover, tight linkage was observed between DHPS mutations and high-level resistance in the 16 progeny of a genetic cross between sulfadoxine-sensitive (HB3) and sulfadoxine-resistant (Dd2) parents. However, we also demonstrate a profound influence of exogenous folate on IC50 values, which, under physiological conditions, may have a major role in determining resistance levels. Importantly, this phenotype does not segregate with dhps genotypes in the cross, but shows complete linkage to the two alleles of the dihydrofolate reductase (dhfr) gene inherited from the parental lines. However, in unrelated lines, this folate effect correlates less well with DHFR sequence, indicating that the gene responsible may be closely linked to dhfr, rather than dhfr itself. These results have major implications for the acquisition of Fansidar resistance by malaria parasites.
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              Toxoplasmosis.

              Eskild Petersen (2007)
              Infections with Toxoplasma gondii occur worldwide, but are especially prevalent in Europe, South America and Africa. The primary problem for the diagnosis of T. gondii infection is long-lasting IgM-antibodies, thus the presence of T. gondii-specific IgM-antibodies do not necessarily indicate an acute infection. The use of a Toxoplasma-specific IgG-avidity ratio, differentiated Western blots and two-dimensional immunoblots usually resolves diagnostic problems. There is no consensus on the best strategy to control congenital toxoplasmosis. Recent European prospective, but descriptive, studies including a meta-analysis of existing cohorts have found a surprisingly small effect on maternal-fetal transmission and clinical signs in children treated for T. gondii infection diagnosed by pre- and neonatal screening programmes. No randomised studies exist on the treatment of T. gondii infection in pregnant women and newborn children with congenital toxoplasmosis. Atovaquone is the most promising new drug available, but is not yet approved for use in pregnant women and small children.
              Article 0 comments Cited 42 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Herbert B. Tanowitz: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 24 January 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 1
                Electronic Location Identifier: e0170689
                Affiliations
                [1 ]Laboratório de Toxoplasmose, Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brasil
                [2 ]Laboratório de Genômica de Parasitos, Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brasil
                Yeshiva University Albert Einstein College of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: LAS DCB RWAV.

                • Formal analysis: LAS JLRC.

                • Funding acquisition: LAS RWAV.

                • Investigation: LAS.

                • Methodology: LAS DCB RWAV.

                • Project administration: LAS.

                • Resources: RWAV DCB.

                • Supervision: RWAV.

                • Validation: LAS JLRC RWAV.

                • Visualization: LAS DCB JLRC RWAV.

                • Writing – original draft: LAS.

                • Writing – review & editing: LAS DCB JLRC RWAV.

                Article
                Publisher ID: PONE-D-16-29384
                DOI: 10.1371/journal.pone.0170689
                PMC ID: 5261777
                PubMed ID: 28118394
                SO-VID: c934dae0-ebd4-42a3-b6c3-aef365557250
                Copyright © © 2017 Silva et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 16 August 2016
                Date accepted : 2 January 2017
                Page count
                Figures: 1, Tables: 4, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;
                Award ID: 150956/2014-2
                Award Recipient :
                LAS was supported by a post doctoral fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) grant 150956/2014-2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Protozoans
                Subject: Parasitic Protozoans
                Subject: Toxoplasma
                Subject: Toxoplasma Gondii
                Subject: Medicine and Health Sciences
                Subject: Parasitic Diseases
                Subject: Protozoan Infections
                Subject: Toxoplasmosis
                Subject: Biology and Life Sciences
                Subject: Parasitology
                Subject: Parasite Groups
                Subject: Apicomplexa
                Subject: Tachyzoites
                Subject: Research and Analysis Methods
                Subject: Immunologic Techniques
                Subject: Immunoassays
                Subject: Enzyme-Linked Immunoassays
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Mutation
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Subject: Medicine and Health Sciences
                Subject: Hematology
                Subject: Blood
                Subject: Research and analysis methods
                Subject: Database and informatics methods
                Subject: Bioinformatics
                Subject: Sequence analysis
                Subject: DNA sequence analysis
                Subject: Research and Analysis Methods
                Subject: Computational Techniques
                Subject: Split-Decomposition Method
                Subject: Multiple Alignment Calculation
                Custom metadata
                Data Availability All relevant data are within the paper. All DNA sequences files are available from the GenBank database (GenBank accession numbers for each sequences group are in Materials and Methods section within the paper).

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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