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Aminoquinolines susceptibility of Plasmodium falciparum clones from Nouna Burkina Faso Africa

Agustar, Hani Kartini Binti

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We observed a declining trend in malaria transmission at Nouna, Burkina Faso during the rainy season from 2009-2011. Single and mixed infections for Plasmodium falciparum and Plasmodium malariae were significantly reduced compared to the baseline data (rainy season 2000) and a lower prevalence of P. malariae was associated with a reduced transmission intensity. Microscopic examination has a lower detection limit and is associated with under-estimation of parasite burden, which suggested the use of molecular diagnosis such as PCR as a more sensitive method in determining the prevalence of malaria infections.

Amodiaquine (AQ) is an antimalarial compound chemically and functionally related to chloroquine (CQ). Currently, it is used in combination with artesunate (AS) as the first choice to treat uncomplicated P. falciparum malaria in some countries in Africa and South America. Chloroquine-resistant parasites and cross-resistance between CQ and AQ or its active metabolite Desethyl-amodiaquine (DQ) have been observed in Burkina Faso. pfcrt and pfmdr1 are genes genetically associated with the resistance mechanism and the underlying mechanisms for cross-resistance are still under debate. The main aim of this study was to assess the susceptibility patterns of clonal field isolates P. falciparum compared to reference laboratory strains (Dd2 and HB3). Blood samples from 402 patients from the village Bourasso, Nouna, Burkina Faso were analysed. Genomic DNA was extracted from filter papers using the Chelex-100 method and different Plasmodium species were analysed by microscopy and species-specific nested-PCR.

The mutation in pfcrt which was associated with CQ and AQ resistance was analysed using pyrosequencing, and in vitro susceptibility of clonal parasites to CQ, AQ and DQ was determined. Three different phenotypes of P. falciparum (S9, S47, S173) based on the IC50 values were cultured and the clonal lines were obtained. All clones from S9 and S47 harboured pfcrt CVIET haplotypes while all clones from S173 were CVMNK haplotype. The clones from S9 showed higher IC50 values on average to CQ and AQ compared to S47 clonal parasites. Some clones were sensitive to DQ for S9 and all were sensitive in clonal lines for sample 47. Clonal parasites from S173 has lower IC50 values towards CQ. Responses to CQ, AQ and DQ varied between the clones. Clear cross-resistance were observed in clonal lines S9, eg. 9C9, 9C7, 9H8 and in clone S47E8. There was a moderate correlation between AQ and DQ and a weaker correlation between AQ and CQ. Cross resistance exists but not high in the clonal lines.

After a consistence result of IC50, 9C6, 47C7 and 173D3 were selected for the drug accumulation study. Accumulation of CQ and AQ does not always correlate with IC50. It appeared that clones accumulating high levels of CQ and AQ were susceptible to CQ and AQ respectively, while clones accumulating lower CQ and AQ were resistant. High CQ and AQ IC50 values were associated with lower amounts of drug uptake and the two response parameters reciprocally correlated to each other. Long-term and continuous culture can cause loss of the resistance phenotype. From the observations and findings of this study, we concluded that Pfcrt plays a major role in the resistance to CQ and AQ and we suggest that one or more genes or SNPs may be involved in AQ drug resistance.

There were no resistant clones isolated from the in-vitro selection strategy after challenge with 60 nM DQ but suggested dormant parasites to DQ developed after the exposure. After investigation using quantitative recrudescence assays, the parasites were not dormant but were in fact dead. Several strategies and processes could be improved for future studies to select for AQ resistant parasites.

Item Type: Dissertation
Supervisor: Jaenisch, PD. Dr. Thomas
Date of thesis defense: 11 June 2018
Date Deposited: 20 Jun 2018 10:07
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics

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  • Aminoquinolines susceptibility of Plasmodium falciparum clones from Nouna Burkina Faso Africa. (deposited 20 Jun 2018 10:07) [Currently Displayed]
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