Publicação
Evaluation of novel molecular markers for monitoring drug resistence in Plasmodium falciparum malaria
| Resumo: | The human malaria parasite Plasmodium falciparum is acquiring resistance to most drugs it has encountered, including the recently deployed Artemisinin Combination Therapy, on which much hope has been laid. Molecular markers for monitoring the evolution of resistance are, therefore, urgently required. Our group has recently made use of a rodent malaria model to identify a number of novel genetic markers of antimalarial drug resistance, namely a clathrin mu adaptor gene (pfcmu) involved in artemisinin resistance and an amino acid transporter gene (pfaat1) underlying chloroquine resistance. The main aim of this thesis was to characterize and evaluate the contribution of the above genes to drug resistance in natural parasite populations of P. falciparum isolates from three endemic areas: Rwanda, Democratic Republic of Sao Tomé & Principe (DRSTP) and Brazil. The global diversity of pfcmu and pfaat1 was determined, resulting in the identification of several polymorphisms. The pfaat1 gene appears to be highly conserved and no correlations were found between this gene and the in vitro resistance to 4-aminoquinolines. In contrast to pfaat1, the pfcmu gene was genetically diverse, with nine Single Nucleotide Polymorphisms and three different insertions identified across all isolates inspected. Samples could be grouped in to fourteen different pfcmu haplotypes, whose diversity was higher in both African sites than in Brazil (Hd = 0.964 ± 0.077, 0.750 ± 0.139 and 0.250 ± 0.180 in Rwanda, DRSTP and Brazil, respectively). Some of the identified polymorphisms showed geographical specificity. We found a significant association between a pfcmu G479A genotype in Rwanda samples and the in vitro sensitivity to dyhidroartemisinin (p = 0.0207). These constitute new findings to suggest that polymorphisms in pfcmu can be involved in P. falciparum defence mechanisms against artemisinin derivatives. Thus, further assessment of the gene in artemisinin responses is a top priority, in the context of effective surveillance of artemisinin resistance. |
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| Autores principais: | Henriques, Gisela Cristina Lourenço |
| Assunto: | Microbiologia Plasmodium falciparum Malária falciparum Malária Resistência a medicamentos Marcadores biológicos Teses de mestrado - 2010 |
| Ano: | 2010 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | The human malaria parasite Plasmodium falciparum is acquiring resistance to most drugs it has encountered, including the recently deployed Artemisinin Combination Therapy, on which much hope has been laid. Molecular markers for monitoring the evolution of resistance are, therefore, urgently required. Our group has recently made use of a rodent malaria model to identify a number of novel genetic markers of antimalarial drug resistance, namely a clathrin mu adaptor gene (pfcmu) involved in artemisinin resistance and an amino acid transporter gene (pfaat1) underlying chloroquine resistance. The main aim of this thesis was to characterize and evaluate the contribution of the above genes to drug resistance in natural parasite populations of P. falciparum isolates from three endemic areas: Rwanda, Democratic Republic of Sao Tomé & Principe (DRSTP) and Brazil. The global diversity of pfcmu and pfaat1 was determined, resulting in the identification of several polymorphisms. The pfaat1 gene appears to be highly conserved and no correlations were found between this gene and the in vitro resistance to 4-aminoquinolines. In contrast to pfaat1, the pfcmu gene was genetically diverse, with nine Single Nucleotide Polymorphisms and three different insertions identified across all isolates inspected. Samples could be grouped in to fourteen different pfcmu haplotypes, whose diversity was higher in both African sites than in Brazil (Hd = 0.964 ± 0.077, 0.750 ± 0.139 and 0.250 ± 0.180 in Rwanda, DRSTP and Brazil, respectively). Some of the identified polymorphisms showed geographical specificity. We found a significant association between a pfcmu G479A genotype in Rwanda samples and the in vitro sensitivity to dyhidroartemisinin (p = 0.0207). These constitute new findings to suggest that polymorphisms in pfcmu can be involved in P. falciparum defence mechanisms against artemisinin derivatives. Thus, further assessment of the gene in artemisinin responses is a top priority, in the context of effective surveillance of artemisinin resistance. |
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