Tolerance Of Plasmodium Falciparum To Artemetherlumefantrine In The Gambia
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Date
2020-12
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Publisher
University Of Ghana
Abstract
Antimalarial drug resistance contributes significantly to obstacles in reducing the global burden
of malaria especially in sub-Saharan Africa (sSA) where the disease is most prevalent.
Resistance to artemisinin-based combination therapies (ACTs), the only recommended
frontline drugs for the treatment of uncomplicated malaria is now widespread in South East
Asia (SEA). However, ACTs remain efficacious in sSA though in vivo delayed parasite
clearance and in vitro reduced susceptibility to both components of the drug has been reported.
Resistance to ACTs is therefore anticipated especially with its sustained use in endemic regions
and the recent report of the emergence of de novo Pfk13 mutation that is now spreading in
Rwanda. In The Gambia where artemether-lumefantrine (AL) is the first-line drug used for
over 10 years, a steady increase in parasite tolerance to lumefantrine (LUM) was observed over
a period of 4 years which strongly correlated with reported directional selection on a cysteine
desulfarase gene (Pfnfs1). These findings are concerning and require continuous drug
surveillance to track spontaneous development of AL resistant parasites and determine
pathways to resistance development.
This study therefore sought to investigate the prevalence and mechanisms of parasite tolerance
to AL in The Gambia. A novel ex vivo drug susceptibility assay suitable to simultaneously
assess parasite responses to both drugs used in AL was developed and used to assess drug
susceptibility profiles of circulating parasites in western Gambia. This assay was then used to
confirm identified potent compounds from the Medicines for Malaria Venture pathogen box
effective against the erythrocytic stages of the parasite for future development into new
antimalarial drugs. The prevalence of known drug resistance markers was assessed and novel
markers that could be associated with drug resistance identified using both regression analysis
and GWAS approach. Finally, CRISPR-Cas9 genome editing was used to functionally validate
Pfnfs1 for its involvement in LUM tolerance using gene editing approaches. Antimalarial drug resistance contributes significantly to obstacles in reducing the global burden
of malaria especially in sub-Saharan Africa (sSA) where the disease is most prevalent.
Resistance to artemisinin-based combination therapies (ACTs), the only recommended
frontline drugs for the treatment of uncomplicated malaria is now widespread in South East
Asia (SEA). However, ACTs remain efficacious in sSA though in vivo delayed parasite
clearance and in vitro reduced susceptibility to both components of the drug has been reported.
Resistance to ACTs is therefore anticipated especially with its sustained use in endemic regions
and the recent report of the emergence of de novo Pfk13 mutation that is now spreading in
Rwanda. In The Gambia where artemether-lumefantrine (AL) is the first-line drug used for
over 10 years, a steady increase in parasite tolerance to lumefantrine (LUM) was observed over
a period of 4 years which strongly correlated with reported directional selection on a cysteine
desulfarase gene (Pfnfs1). These findings are concerning and require continuous drug
surveillance to track spontaneous development of AL resistant parasites and determine
pathways to resistance development.
This study therefore sought to investigate the prevalence and mechanisms of parasite tolerance
to AL in The Gambia. A novel ex vivo drug susceptibility assay suitable to simultaneously
assess parasite responses to both drugs used in AL was developed and used to assess drug
susceptibility profiles of circulating parasites in western Gambia. This assay was then used to
confirm identified potent compounds from the Medicines for Malaria Venture pathogen box
effective against the erythrocytic stages of the parasite for future development into new
antimalarial drugs. The prevalence of known drug resistance markers was assessed and novel
markers that could be associated with drug resistance identified using both regression analysis
and GWAS approach. Finally, CRISPR-Cas9 genome editing was used to functionally validate
Pfnfs1 for its involvement in LUM tolerance using gene editing approaches.
Keywords:
Malaria, antimalarial drug resistance, ex vivo drug assays, high throughput screening
genotyping, functional analysis, association studies
Description
PhD. Molecular Cell Biology Of Infectious Diseases
Keywords
Gambia, Artemetherlumefantrine, Plasmodium Falciparum, Malaria, antimalarial drug resistance